Imidazolyl-3,5-di-(diphenyl-butylsilyloxy) carboxylic acid ester intermediates

ABSTRACT

Compounds of the formula ##STR1## and the pharmaceutically acceptable acid addition salts thereof, wherein the various substituents are defined herein below, 
     the use thereof for inhibiting cholesterol biosynthesis and lowering the blood cholesterol level and, therefore, in the treatment of hyperlipoproteinemia and atherosclerosis, pharmaceutical compositions comprising such compounds and processes for and intermediates in the synthesis of such compounds.

This is a division of application Ser. No. 863,267, filed May 14, 1986, now abandoned, which in turn is a continuation-in-part of Ser. No. 736,679, filed May 22, 1985, now U.S. Pat. No. 4,668,794.

This invention relates to compounds of the formula ##STR2## and the pharmaceutically acceptable acid addition salts thereof, wherein

R₁ is C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl, adamantyl-1 or ##STR3## wherein R₄, R₅ and R₆ are as defined below, R₂ is C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl, adamantyl-1 or ##STR4## wherein R₇, R₈ and R₉ are as defined below, R₃ is hydrogen, C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl, adamantyl-1, styryl or ##STR5## wherein R₁₀, R₁₁ and R₁₂ are as defined below, X is --(CH₂)_(m) --, --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH--, wherein m is 0, 1, 2 or 3, and

Z is ##STR6## wherein each R₁₅ is primary or secondary C₁₋₆ alkyl not containing an asymmetric carbon atom, the two R₁₅ 's being the same, or

the two R₁₅ 's taken together are --(CH₂)_(q) --, wherein q is 2 or 3,

R₁₃ is hydrogen or C₁₋₃ alkyl, and

R₁₄ is hydrogen, R₁₆ or M,

wherein R₁₆ is a physiologically acceptable ester group, and

M is a pharmaceutically acceptable cation,

with the proviso that Z may be a group of Formula c only when (i) X is --CH═CH-- or --CH₂ --CH═CH--, (ii) R₁₃ is C₁₋₃ alkyl or (iii) both (i) and (ii),

wherein

each of R₄, R₇ and R₁₀ is independently hydrogen, C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl, C₁₋₃ alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy,

each of R₅, R₈ and R₁₁ is independently hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, trifluoromethyl, fluoro, chloro, bromo, --COOR₁₇, --N(R₁₉)₂, phenoxy or benzyloxy,

wherein R₁₇ is hydrogen, R₁₈ or M,

wherein R₁₈ is C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl or benzyl, and

M is as defined above, and

each R₁₉ is independently C₁₋₆ alkyl not containing an asymmetric carbon atom, and

each of R₆, R₉ and R₁₂ is independently hydrogen, C₁₋₂ alkyl, C₁₋₂ alkoxy, fluoro or chloro, with the provisos that not more than one substituent on each of Rings A, B and C independently is trifluoromethyl, not more than one substituent on each of Rings A, B and C independently is phenoxy, and not more than one substituent on each of Rings A, B and C independently is benzyloxy,

with the provisos that (1) when Z is a group of Formula c wherein Q is a group of Formula cb, the compound is in free base form and either (i) R₁₄ is R₁₆ and each R₁₇ is independently R₁₈ or (ii) R₁₄ is M and each R₁₇ is independently R₁₈ or M and (2) when (i) R₁₄ or at least one R₁₇ is M or (ii) R₁₄ and at least one R₁₇ are M, the compound is in free base form,

processes for and intermediates in the synthesis thereof, pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof, and the use of the compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof for inhibiting cholesterol biosynthesis and lowering the blood cholesterol level and, therefore, in the treatment of hyperlipoproteinemia and atherosclerosis.

By the term "physiologically acceptable ester group" is meant a group which, together with the --COO-- radical to which it is attached, forms an ester group which is physiologically acceptable. The preferred such groups are the physiologically acceptable and hydrolyzable ester groups. By the term "physiologically acceptable and hydrolyzable ester group" is meant a group which, together with the --COO-- radical to which it is attached, forms an ester group which is physiologically acceptable and hydrolyzable under physiological conditions to yield a compound of Formula I wherein R₁₄ is hydrogen and an alcohol which itself is physiologically acceptable, i.e., non-toxic, at the desired dosage level, and which, preferably, is free of centers of asymmetry. Examples of such groups are C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl and benzyl, collectively referred to as R'₁₆.

The compounds of Formula I except those wherein R₁₄ and/or one or more R₁₇ 's are M may be converted into pharmaceutically acceptable acid addition salt form. By the term "pharmaceutically acceptable acid addition salts" is meant those acid addition salts that are physiologically acceptable, i.e., that do not significantly increase the toxicity of the basic compound or otherwise adversely affect its pharmacological activity. Such pharmaceutically acceptable acid addition salts are included within the scope of this invention. Included are salts with strong organic acids, e.g., the methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate salts, and salts with strong inorganic acids, e.g., the hydrochloride, hydrobromide and sulfate salts. The preferred strong acids are those having a pK (the pK of at least the initial dissociation step if the acid has more than one) in water at 25° C. below about 3, more preferably below about 2 and most preferably below about 1.

For the avoidance of doubt, throughout this specification it is the right-hand side of the X radical that is attached to the Z group.

As is self-evident to those in the art, each compound of Formula I wherein Z is a group of Formula a or b (and every subscope and species thereof) has two centers of asymmetry (the two carbon atoms bearing the hydroxy groups in the group of Formula a and the carbon atom bearing the hydroxy group and the carbon atom having the free valence in the group of Formula b) and, therefore, there are four stereoisomeric forms (enantiomers) of each compound (two racemates or pairs of diastereoisomers), provided that R₁₄ does not contain any center of asymmetry. The four stereoisomers may be designated as the R,R, R,S, S,R and S,S enantiomers, all four stereoisomers being within the scope of the invention. When R₁₄ contains one or more centers of asymmetry, there are eight or more stereoisomers. On the other hand, each compound of Formula I wherein Z is a group of Formula c (and every subscope and species thereof) has a single center of asymmetry (the carbon atom bearing the hydroxy group in the group of Formula c) and, therefore, there are two enantiomers of each compound, provided that R₁₄ does not contain any center of asymmetry. The two stereoisomers may be designated as the 3R and 3S enantiomers, both being within the scope of this invention. Since it is preferred that R₁₄ not contain a center of asymmetry and for reasons of simplicity, in both cases any additional stereoisomers resulting from the presence of one or more centers of asymmetry in R₁₄ will usually be ignored, it being assumed that R₁₄ is free of centers of asymmetry. Each pharmaceutically acceptable acid addition salt contains the same number of centers of asymmetry as the corresponding free base provided that the acid does not contain any center asymmetry.

The compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof may be divided into four subgroups, Groups IA, IB, IC and ID, based upon the significances of R₁ and R₂.

    ______________________________________                                         Group    R.sub.1         R.sub.2                                               ______________________________________                                         IA       Other Than Ring A                                                                              Ring B                                                IB       Ring A          Other Than Ring B                                     IC       Ring A          Ring B                                                ID       Other Than Ring A                                                                              Other Than Ring B                                     ______________________________________                                    

The compounds and pharmaceutically acceptable acid addition salts of each of Groups IA, IB, IC and ID may be divided into three subgroups based upon the significance of Z viz., Groups IAa, IAb and IAc (those of Group IA wherein Z is a group of Formula a, b or c, respectively), Groups IBa, IBb and Ibc (those of Group IB wherein Z is a group of Formula a, b or c, respectively), Groups ICa, ICb and ICc (those of Group IC wherein Z is a group of Formula a, b or c, respectively) and Groups IDa, IDb and IDc (those of Group ID wherein Z is a group of Formula a, b or c, respectively).

Preferably, one of R₁ and R₂ is C₁₋₆ alkyl not containing an asymmetric carbon atom and the other is Ring A (if R₁) or Ring B (if R₂). R₃ is preferably Ring C. More preferably, the preferences set forth in the preceding two sentences occur simultaneously.

Also preferably, at least one of R₂ and R₃ is other than tertiary alkyl.

Q is preferably --CO--.

R₁ is preferably R'_(1x), where R'_(1x) is C₁₋₆ alkyl not containing an asymmetric carbon atom, more preferably R"_(1x), where R"_(1x) is C₁₋₃ alkyl, n-butyl or i-butyl, even more preferably R"'_(1x), where R"'_(1x) is C₁₋₃ alkyl, and most preferably i-propyl; or

R₁ is preferably R'_(1y), where R'_(1y) is Ring A, more preferably R"_(1y), where R"_(1y) is Ring A wherein R₄ is R'₄, R₅ is R'₅, and R₆ is R'₆, even more preferably R"'_(1y), where R"'_(1y) is Ring A wherein R₄ is R"₄, R₅ is R"₅, and R₆ is R'₆, and most preferably R""_(1y), where R""_(1y) is Ring A wherein R₄ is R"₄, R₅ is R"₅, and R₆ is hydrogen, especially phenyl, 3,5-dimethylphenyl or 4-fluorophenyl and more especially 4-fluorophenyl.

R₂ is preferably R'_(2x) where R'_(2x) is Ring B, more preferably R"_(2x), where R"_(2x) is Ring B wherein R₇ is R'₇, R₈ is R'₈, and R₉ is R'₉, even more preferably R"'_(2x), where R"'_(2x) is Ring B wherein R₇ is R"₇, R₈ is R"₈, and R₉ is R'₉, and most preferably R""_(2x), where R""_(2x) is Ring B wherein R₇ is R"₇, R₈ is R"₈, and R₉ is hydrogen, especially phenyl, 3,5-dimethylphenyl or 4-fluorophenyl and more especially 4-fluorophenyl; or

R₂ is preferably R'_(2y), where R'_(2y) is C₁₋₆ alkyl not containing an asymmetric carbon atom, more preferably R"_(2y), where R"_(2y) is C₁₋₃ alkyl, n-butyl or i-butyl, even more preferably R"'_(2y), where R"'_(2y) is C₁₋₃ alkyl, and most preferably i-propyl.

R₃ is preferably R'₃, where R'₃ is C₁₋₆ alkyl not containing an asymmetric carbon atom, cyclohexyl or Ring C, more preferably R"₃, where R"₃ is Ring C, even more preferably R"'₃, where R"'₃ is Ring C wherein R₁₀ is R'₁₀, R₁₁ is R'₁₁, and R₁₂ is R'₁₂, and most preferably R""₃, where R""₃ is Ring C wherein R₁₀ is R"₁₀, R₁₁ is R"₁₁, and R₁₂ is R'₁₂, especially phenyl.

Each of R₄ and R₇ is preferably R'₄ and R'₇, respectively, where each of R'₄ and R'₇ is independently hydrogen, C₁₋₃ alkyl, fluoro, chloro or bromo, more preferably R"₄ and R"₇, respectively, where each of R"₄ and R"₇ is independently hydrogen, methyl or fluoro, and most preferably hydrogen or fluoro, especially 4-fluoro.

Each of R₅ and R₈ is preferably R'₅ and R'₈, respectively, where each of R'₅ and R'₈ is independently hydrogen, C₁₋₂ alkyl, fluoro or chloro, more preferably R"₅ and R"₈, respectively, where each of R"₅ and R"₈ is independently hydrogen or methyl, and most preferably hydrogen.

Each of R₆ and R₉ is preferably R'₆ and R'₉, respectively, where each of R'₆ and R'₉ is independently hydrogen or methyl, and most preferably hydrogen.

R₁₀ is preferably R'₁₀, where R'₁₀ is hydrogen, C₁₋₃ alkyl, C₁₋₂ alkoxy, trifluoromethyl, fluoro, chloro, bromo or phenyl, more preferably R"₁₀, where R"₁₀ is hydrogen, methyl or fluoro, and most preferably hydrogen.

R₁₁ is preferably R'₁₁, wherein R'₁₁ is hydrogen, C₁₋₂ alkyl, fluoro, chloro, bromo, --COOR'₁₇ or --N(R'₁₉)₂, more preferably R"₁₁, where R"₁₁ is hydrogen or methyl, and most preferably hydrogen.

R₁₂ is preferably R'₁₂, where R'₁₂ is hydrogen or methyl, and most preferably hydrogen.

Preferably, each of Rings A, B and C independently bears a maximum of one substituent selected from the group consisting of t-butyl, trifluoromethyl, phenyl, phenoxy and benzyloxy. More preferably, when any two or all three of the substituents on Ring A [R₄ (R'₄, etc.), R₅ (R'₅, etc.) and R₆ (R'₆, etc.)], Ring B [R₇ (R'₇, etc.), R₈ (R'₈, etc.) and R₉ (R'₉, etc.)] and Ring C [R₁₀ (R'₁₀, etc.), R₁₁ (R'₁₁, etc.) and R₁₂ (R'₁₂, etc.)] independently are ortho to each other, at least one member of each pair that are ortho to each other is a member of the group consisting of hydrogen, methyl, methoxy, fluoro and chloro. Also more preferably, at least one of the ortho positions of each of Rings A, B and C independently has a member of the group consisting of hydrogen, fluoro and methyl.

R₁₃ is preferably R'₁₃, where R'₁₃ is hydrogen or methyl, and most preferably hydrogen.

R₁₄ is preferably R'₁₄, where R'₁₄ is hydrogen, R'₁₆ or M, more preferably R"₁₄, where R"₁₄ is hydrogen, C₁₋₃ alkyl or M, even more preferably R"'₁₄, where R"'₁₄ is hydrogen, C₁₋₂ alkyl or M, and most preferably M, especially sodium.

Preferably, each R₁₅ is C₁₋₃ alkyl or both R₁₅ 's taken together are --(CH₂)_(q) --; more preferably, each R₁₅ is C₁₋₂ alkyl or both R₁₅ 's taken together are --(CH₂)_(q) --; and most preferably, each R₁₅ is C₁₋₂ alkyl.

R₁₆ is preferably a physiologically acceptable and hydrolyzable ester group, more preferably R'₁₆, where R'₁₆ is C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl or benzyl, even more preferably C₁₋₃ alkyl, and most preferably C₁₋₂ alkyl, especially ethyl.

Preferably, each R₁₇ is independently R'₁₇, where R'₁₇ is hydrogen, R'₁₈ or M; more preferably, each R₁₇ is independently R"₁₇, where R"₁₇ is C₁₋₂ alkyl or M.

Also preferably, when a compound contains two or more R₁₇ 's, each R₁₇ is independently R₁₈ (R'₁₈ or C₁₋₂ alkyl) or the R₁₇ 's (R'₁₇ 's or R"₁₇ 's) are identical, each of them being hydrogen or the same M.

More preferably, either (i) R₁₃ is hydrogen, R₁₄ (if present) is R'₁₆, and each R₁₇ is independently R₁₈ or (ii) R₁₄ (if present) and each R₁₇ are identical, each of them being hydrogen or the same M.

Preferably, each R₁₈ is independently R'₁₈, where R'₁₈ is C₁₋₃ alkyl; more preferably, each R₁₈ is independently C₁₋₂ alkyl.

Each R₁₉ is preferably R'₁₉, where each R'₁₉ is independently C₁₋₂ alkyl.

Any --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH-- as X is preferably trans, i.e., (E).

X is preferably X', where X' is --CH₂ CH₂ -- or --CH═CH--, more preferably --CH═CH--, and most preferably ##STR7## i.e., (E)--CH═CH--.

Z is preferably a group of Formula a wherein R₁₃ is R'₁₃, and R₁₄ is R'₁₄, a group of Formula b wherein R₁₃ is R'₁₃ or a group of Formula c wherein Q is --CO--, R₁₃ is R'₁₃, and R₁₄ is R'₁₄, more preferably a group of Formula a wherein R₁₃ is hydrogen, and R₁₄ is R"₁₄, a group of Formula b wherein R₁₃ is hydrogen or a group of Formula c wherein Q is --CO--, R₁₃ is hydrogen, and R₁₄ is R"₁₄, and most preferably a group of Formula a wherein R₁₃ is hydrogen, and R₁₄ is R"'₁₄, preferably C₁₋₂ alkyl or M, more preferably ethyl or M, most preferably M and especially M'.

m is preferably m', where m' is 2 or 3, and most preferably 2.

Each M is preferably free from centers of asymmetry and is more preferably M', i.e., sodium, potassium or ammonium, and most preferably sodium. For simplicity, each formula in which an M appears has been written as if M were monovalent and, preferably, it is. However, M may also be divalent or trivalent and, when it is, it balances the charge of two or three carboxy groups, respectively. Thus, Formula I and every other formula containing an M embraces compounds wherein M is divalent or trivalent, e.g., compounds containing two or three monocarboxylate-containing anions per cation M. Preferably, when a compound contains two or more M's, they are the same.

As between otherwise identical compounds of Formula I and pharmaceutically acceptable acid addition salts thereof, those wherein Z is a group of Formula a are generally preferred over those wherein Z is a group of Formula b or c.

Insofar as the compounds of Groups IAa, IBa, ICa and IDa and the pharmaceutically acceptable acid addition salts thereof and each of the subgroups thereof are concerned, the erythro isomers are preferred over the threo isomers, erythro and threo referring to the relative positions of the hydroxy groups in the 3- and 5-positions of the group of Formula a.

Insofar as the compounds of Groups IAb, IBb, ICb and IDb and the pharmaceutically acceptable acid addition salts thereof and each of the subgroups thereof are concerned, the trans lactones are generally preferred over the cis lactones, cis and trans referring to the relative positions of R₁₃ and the hydrogen atom in the 6-position of the group of Formula b.

The preferred stereoisomers of the compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof having only two centers of asymmetry wherein X is a direct bond, --CH═CH-- or --CH₂ --CH═CH--, and Z is a group of Formula a are the 3R,5S isomer and the racemate of which it is a constituent, i.e., the 3R,5S-3S,5R (erythro) racemate.

The preferred stereoisomers of the compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof having only two centers of asymmetry wherein X is --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂ CH₂ -- or --CH═CH--CH₂ --, and Z is a group of Formula a are the 3R,5R isomer and the racemate of which it is a constituent, i.e., the 3R,5R-3S,5S (erythro) racemate.

The preferences set forth in the preceding two paragraphs also apply to the compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof wherein Z is a group of Formula a having more than two centers of asymmetry and represent the preferred configurations of the indicated positions.

The preferred stereoisomers of the compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof wherein X is a direct bond, --CH═CH-- or --CH₂ --CH═CH--, and Z is a group of Formula b are the 4R,6S and 4R,6R isomers and the racemate of which each is a constituent, i.e., the 4R,6S-4S,6R (trans lactone) and 4R,6R-4S,6S (cis lactone) racemates, with the 4R,6S isomer and the racemate of which it is a constituent being more preferred and the 4R,6S isomer being most preferred.

The preferred stereoisomers of the compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof wherein X is --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂ CH₂ -- or --CH═CH--CH₂ --, and Z is a group of Formula b are the 4R,6R and 4R,6S isomers and the racemate of which each is a constituent, i.e., the 4R,6R-4S,6S (trans lactone) and 4R,6S-4S,6R (cis lactone) racemates, with the 4R,6R isomer and the racemate of which it is a constituent being more preferred and the 4R,6R isomer being most preferred.

The preferred stereoisomers of the compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof having just one center of asymmetry wherein Z is a group of Formula c are the 3R isomer and the racemate of which it is a constituent, i.e., the 3R-3S racemate, with the 3R isomer being more preferred. These preferences also apply to the compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof wherein Z is a group of Formula c having more than one center of asymmetry and represent the preferred configuration of the indicated position.

Generally, the compounds of Formula I are preferred over the pharmaceutically acceptable acid addition salts of the corresponding compounds.

Each of the preferences set forth above applies, not only to the compounds of Formula I, but also to the compounds of Groups IA, IB, IC and ID and the pharmaceutically acceptable acid addition salts thereof and those of Groups IAa, IAb, IAc, IBa, IBb, IBc, ICa, ICb, ICc, IDa, IDb and IDc as well as to every other subgroup thereof set forth in the specification, e.g., Groups (i) et seq., unless otherwise indicated. When any preference or group contains a variable, the preferred significances of that variable apply to the preference or group in question, unless otherwise indicated.

Preferred subgroups of Groups IAa, IAb, IAc, IBa, IBb and IBc include the compounds and the pharmaceutically acceptable acid addition salts

(i) of Group IAa wherein R₁ is R'_(1x), R₂ is R"_(2x), R₃ is R'₃, R₁₃ is R'₁₃, R₁₄ is R'₁₄, and X is X',

(ii) of (i) wherein R₁ is R"_(1x), R₃ is R"₃, R₁₃ is hydrogen, R₁₄ is R"₁₄, and X is (E)--CH═CH--,

(iii) of (ii) wherein R₃ is R"'₃, and R₁₄ is R"'₁₄,

(iv) of (iii) wherein R₁ is R"'_(1x) (especially i-propyl), R₂ is R"'_(2x), and R₃ is R""₃,

(v)-(viii) of (i)-(iv) wherein R₁₄ is M, preferably M' and especially sodium,

(ix)-(xvi) of (i)-(viii) wherein the hydroxy groups in the 3- and 5-positions of the group of Formula a have the erythro configuration,

(xvii)-(xxiv) the 3R,5S enantiomers of (ix)-(xvi) when X is --CH═CH-- and the 3R,5R enantiomers of (ix) when X is --CH₂ CH₂ --,

(xxv) of Group IAb wherein R₁ is R'_(1x), R₂ is R"_(2x), R₃ is R'₃, R₁₃ is R'₁₃, and X is X',

(xxvi) of (xxv) wherein R₁ is R"_(1x), R₃ is R"₃, R₁₃ is hydrogen, and X is (E)--CH═CH--,

(xxvii) of (xxvi) wherein R₃ is R"'₃,

(xxviii) of (xxvii) wherein R₁ is R"'_(1x) (especially i-propyl), R₂ is R"'_(2x), and R₃ is R""₃,

(xxix)-(xxxii) of (xxv)-(xxviii) wherein R₁₃ and the hydrogen atom in the 6-position of the group of Formula b are trans to each other, i.e., the trans lactones,

(xxxiii)-(xxxvi) the 4R,6S enantiomers of (xxix)-(xxxii) when X is --CH═CH-- and the 4R,6R enantiomers of (xxix) when X is --CH₂ CH₂ --,

(xxxvii) of Group IAc wherein R₁ is R'_(1x), R₂ is R"_(2x), R₃ is R'₃, R₁₃ is R'₁₃, R₁₄ is R'₁₄, each R₁₅ is C₁₋₃ alkyl or both R₁₅ 's taken together are --(CH₂)_(q) --, and X is X',

(xxxviii) of (xxxvii) wherein R₁ is R"_(1x), R₃ is R"₃, R₁₃ is hydrogen, R₁₄ is R"₁₄, each R₁₅ is C₁₋₂ alkyl or both R₁₅ 's taken together are --(CH₂)_(q) --, and X is (E)--CH═CH--,

(xxxix) of (xxxviii) wherein R₃ is R"'₃, R₁₄ is R"'₁₄, and each R₁₅ is C₁₋₂ alkyl,

(xl) of (xxxix) wherein R₁ is R"'_(1x) (especially i-propyl), R₂ is R"'_(2x), and R₃ is R""₃,

(xli)-(xliv) of (xxxvii)-(xl) wherein Q is --CO--,

(xlv)-(lii) of (xxxvii)-(xliv) wherein R₁₄ is M, preferably M' and especially sodium,

(liii)-(lxviii) the 3R enantiomers of (xxxvii)-(lii),

(lxix) of Group IBa wherein R₁ is R"_(1y), R₂ is R'_(2y), R₃ is R'₃, R₁₃ is R'₁₃, R₁₄ is R'₁₄, and X is X',

(lxx) of (lxix) wherein R₂ is R"_(2y), R₃ is R"₃, R₁₃ is hydrogen, R₁₄ is R"₁₄, and X is (E)--CH═CH--,

(lxxi) of (lxx) wherein R₃ is R"'₃, and R₁₄ is R"'₁₄,

(lxxii) of (lxxi) wherein R₁ is R"'_(1y), R₂ is R"'_(2y) (especially i-propyl), and R₃ is R""₃,

(lxxiii)-(lxxvi) of (lxix)-(lxxii) wherein R₁₄ is M, preferably M', and especially sodium,

(lxxvii)-(lxxxiv) of (lxix)-(lxxvi) wherein the hydroxy groups in the 3- and 5-positions of the group of Formula a have the erythro configuration,

(lxxxv)-(xcii) the 3R,5S enantiomers of (lxxvii)-(lxxxiv) when X is --CH═CH-- and the 3R,5R enantiomers of (lxxvii) when X is --CH₂ CH₂ --,

(xciii) of Group IBb wherein R₁ is R"_(1y), R₂ is R'_(2y), R₃ is R'₃, R₁₃ is R'₁₃, and X is X',

(xciv) of (xciii) wherein R₂ is R"_(2y), R₃ is R"₃, R₁₃ is hydrogen, and X is (E)--CH═CH--,

(xcv) of (xciv) wherein R₃ is R"'₃,

(xcvi) of (xcv) wherein R₁ is R"'_(1y), R₂ is R"'_(2y) (especially i-propyl), and R₃ is R""₃,

(xcvii)-(c) of (xciii)-(xcvi) wherein R₁₃ and the hydrogen atom in the 6-position of the group of Formula b are trans to each other,

(ci)-(civ) and 4R,6S enantiomers of (xcvii)-(c) when X is --CH═CH-- and the 4R,6R enantiomers of (xcvii) when X is --CH₂ CH₂ --,

(cv) of Group IBc wherein R₁ is R"_(1y), R₂ is R'_(2y), R₃ is R'₃, R₁₃ is R'₁₃, R₁₄ is R'₁₄, each R₁₅ is C₁₋₃ alkyl or both R₁₅ 's taken together are --(CH₂)_(q) --, and X is X',

(cvi) of (cv) wherein R₂ is R"_(2y), R₃ is R"₃, R₁₃ is hydrogen, R₁₄ is R"₁₄, each R₁₅ is C₁₋₂ alkyl or both R₁₅ 's taken together are --(CH₂)_(q) --, and X is (E)--CH═CH--,

(cvii) of (cvi) wherein R₃ is R"'₃, R₁₄ is R"'₁₄, and each R₁₅ is C₁₋₂ alkyl,

(cviii) of (cvii) wherein R₁ is R"'_(1y), R₂ is R"'_(2y) (especially i-propyl), and R₃ is R""₃,

(cix)-(cxii) of (cv)-(cviii) wherein Q is --CO--,

(cxiii)-(cxx) of (cv)-(cxii) wherein R₁₄ is M, preferably M' and especially sodium, and

(cxxi)-(cxxxvi) and 3R enantiomers of (cv)-(cxx).

Groups (ix)-(xvi) and (lxxvii)-(lxxxiv) embrace the 3R,5S-3S,5R racemate and the 3R,5S enantiomers when X is --CH═CH--, the 3S,5R enantiomer being least preferred, and the 3R,5R-3S,5S racemate and the 3R,5R and 3S,5S enantiomers when X is --CH₂ CH₂ --, the 3S,5S enantiomer being least preferred.

Groups (xxix)-(xxxii) and (xcvii)-(c) embrace the 4R,6S-4S,6R racemate and the 4R,6S and 4S,6R enantiomers when X is --CH═CH--, the 4S,6R enantiomer being least preferred, and the 4R,6R-4S,6S racemate and the 4R,6R and 4S,6S enantiomers when X is --CH₂ CH₂ --, the 4S,6S enantiomer being least preferred.

Insofar as Groups ICa, ICb and ICc are concerned, the preferred subgroups are those that correspond to Groups (i)-(lxviii) wherein R'_(1x) in Groups (i), (xxv) and (xxxvii) is replaced by R"_(1y), "R₁ is R"_(1x) " is deleted from Groups (ii), (xxvi) and (xxxviii) and "R"'_(1x) (especially i-propyl)" in Groups (iv), (xxviii) and (xl) is replaced by R"'_(1y), i.e., Groups (cxxxvii)-(cciv).

Insofar as Groups IDa, IDb and IDc are concerned, the preferred subgroups are those that correspond to Groups (i)-(lxviii) wherein R"_(2x) in Groups (i), (xxv) and (xxxvii) is replaced by R'_(2y), "R₂ is R"_(2y) " is added to Groups (ii), (xxvi) and (xxxviii), and R"'_(2x) in Groups (iv), (xxviii) and (xl) is replaced by "R"'_(2y) (especially i-propyl)", i.e., Groups (ccv)-(cclxxii).

It goes without saying that all of the provisos set forth above in connection with Formula I apply to Groups (i)-(cclxxii) and any other group set forth in this specification.

A representative group of the compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof are those wherein one of R₁ and R₂ is R'_(1x) and the other is Ring A wherein R₄ is other than bromo and R₅ is other than bromo, --COOR₁₇ and --N(R₁₉)₂ (R₆ being as defined above), R₃ is Ring C wherein R₁₀ is other than bromo and R₁₁ is other than bromo, --COOR₁₇ and --N(R₁₉)₂ (R₁₂ being as defined above), X is X', and Z is a group of Formula a wherein R₁₃ is hydrogen, and R₁₄ is hydrogen, a physiologically acceptable and hydrolyzable ester group or M or a group of Formula b wherein R₁₃ is hydrogen, each of the variables not defined here being as defined above, with the provisos that not more than one substituent on each of Rings A and C independently is trifluoromethyl, not more than one substituent on each of Rings A and C independently is phenoxy, not more than one substituent on each of Rings A and C independently is benzyloxy, and the compounds must be in free base form when Z contains an M. The preferences for each variable and the preferred groups of these compounds and pharmaceutically acceptable acid addition salts are set forth column 3, line 30-column 6, line 33 of U.S. Pat. No. 4,668,794 which are hereby incorporated by reference as if set forth herein in their entirety.

The free bases of each group that embraces both free bases and pharmaceutically acceptable acid addition salts are preferred.

The compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof may be synthesized as follows:

REACTION SCHEME I

The compounds of Formula I wherein any R₁₇ is R₁₈ and either X is --CH═CH-- or --CH₂ --CH═CH--, and Z is a group of Formula b having the 4R,6S configuration or X is --CH₂ CH₂ -- or --CH₂ CH₂ CH₂ --, and Z is a group of Formula b having the 4R,6R configuration may be synthesized by the following series of reactions: ##STR8##

REACTION SCHEME II

The compounds of Formula I wherein any R₁₇ is R₁₈, X is --CH₂ CH₂ --, --CH₂ CH₂ CH₂ --, --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH--, and Z is a group of Formula a wherein R₁₄ is R'₁₆ may be synthesized by the following series of reactions: ##STR9##

REACTION SCHEME III

The compounds of Formula I wherein X is --(CH₂)_(m) -- or (E)--CH═CH--, and (i) any R₁₇ is R₁₈, and Z is a group of Formula a wherein R₁₃ is hydrogen, and R₁₄ is R'₁₆ or (ii) R₁₃ is R_(13a), R₁₄ is M₂.sup.⊕ and any M as R₁₇ is M₂.sup.⊕ may be synthesized by the following series of reactions: ##STR10##

REACTION SCHEME IV

The compounds of Formula I wherein Z is a group of Formula a or b may be converted into the corresponding compounds of Formula I wherein Z has a different significance of Formula a or b, and the compounds of Formula I wherein Z is a group of Formula a or b except those containing an M may be converted into the corresponding pharmaceutically acceptable acid addition salts by the following series of reactions: ##STR11##

REACTION SCHEME V

The compounds of Formula I wherein Z is a group of Formula c may be synthesized by the following series of reactions: ##STR12##

REACTION SCHEME VI

The compounds of Formula XV may be synthesized by the following series of reactions: ##STR13##

REACTION SCHEME VII

The compounds of Formulae II and III and those of Formula LXVIII wherein R_(1a) is R_(1r) may be synthesized by the following series of reactions: ##STR14##

In the foregoing reaction schemes,

HA is a pharmaceutically acceptable acid,

Im is ##STR15## ImA is Im wherein each R₁₇ is independently R₁₈, ImB is Im wherein each R₁₇ is independently R₁₈ or M₂.sup.⊕,

ImC is Im wherein each R₁₇ is independently R₁₈ or M₂.sup.⊕, with the proviso that at least one --COO.sup.⊕ M₂.sup.⊖ group is present,

ImD is Im wherein each R₁₇ is independently hydrogen or R₁₈,

ImE is Im wherein each R₁₇ is independently hydrogen, R₁₈ or M, with the proviso that at least one --COO.sup.⊖ M.sup.⊕ group is present,

ImF is Im wherein each R₁₇ is independently hydrogen or R₁₈, with the proviso that at least one carboxy group is present,

ImG is Im wherein each R₁₇ is independently R₁₈ or M, with the proviso that at least one --COO.sup.⊖ M.sup.⊕ group is present,

ImH is Im wherein each R₁₇ is independently R₁₈ or M,

R_(1a) is R₁ wherein R₁₇ is R₁₈,

R_(1r) is Ring A wherein R₁₇ is R₁₈,

R_(2a) is R₂ wherein R₁₇ is R₁₈,

R_(3a) is R₃ wherein R₁₇ is R₁₈,

R_(3r) is R_(3a), with the proviso that R_(3r) is other than hydrogen,

R_(13a) is C₁₋₃ alkyl, preferably methyl,

each R₂₁ is independently C₁₋₂ alkyl, the two C₁₋₂ alkyl groups preferably being the same,

each R₂₂ is independently C₁₋₃ alkyl, preferably n-C₁₋₃ alkyl, and most preferably C₁₋₂ alkyl,

X₁ is --CH₂ -- or --CH₂ CH₂ --,

X₂ is --CH═CH-- or --CH₂ --CH═CH--, preferably --CH═CH-- and especially (E)--CH═CH--,

X₃ is --CH₂ CH₂ -- or --CH₂ CH₂ CH₂ --, especially --CH₂ CH₂ --,

X₄ is a direct bond or --CH₂ --,

X₅ is --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH--, preferably (E)--CH═CH--, (E)--CH═CH--CH₂ -- or (E)--CH₂ --CH═CH-- and especially (E)--CH═CH--,

X₆ is --(CH₂)_(m) -- or (E)--CH═CH--, especially (E)--CH═CH--,

X₇ is --(CH₂)_(m) --, --CH═CH--, --CH₂ --CH═CH-- or --CH═CH--CH₂ -- when R₁₃ is C₁₋₃ alkyl and is --CH═CH-- or --CH₂ --CH═CH-- when R₁₃ is hydrogen,

Y is chloro or bromo,

Y.sup.⊖ is chloride or bromide,

M₂.sup.⊕ is sodium or potassium, and each of the other variables is as defined above.

    __________________________________________________________________________                                                               Inert                Reaction/                                                 Atmos-               Type   Reagents, Molar Ratios and Comments                                                                    Temperature                                                                              Time   Solvent   phere                __________________________________________________________________________     A (Wittig)                                                                            Alternative a:                                                                 (1)                                                                              1-2 moles strong base, e.g., sodium                                                                  -40°-5° C.,                                                                5-60 min.                                                                             AIO, e.g.,                                                                               Yes                           hydride or pref.  -n-butyllithium, per                                                               -35°--20° C.                                                                      such as toluene                         mole II. Pref., slowly add  -n-butyl-  or, pref., ES                           lithium solution to solution of II.    such as THF                           (2)                                                                              0.65-1.5 moles IV per mole II used in                                                                -55°-25° C.,                                                               0.75-18                                                                               Same as Step                                                                             Yes                           Step 1.               pref. -35°-                                                                       hrs., pref.                                                          -5° C.                                                                            1-4 hrs.                                     Alternative b:                                                                 (1)                                                                              1 mole strong base, pref.  -n-butyllithium                                                           -10°-0° C.                                                                 1-1.5 hrs.                                                                            AIO, pref.                                                                               Yes                           or lithium diisopropylamide, and,      esp. THF                                optionally, 1.75-2 moles lithium chloride                                      per mole III. Add strong base to other                                         reactants.                                                                   (2)                                                                              1-1.2 moles IV per mole III used in Step                                                             -10°-0° C.                                                                 1-12 hrs.                                                                             Same as Step                                                                             Yes                           1.                                                                           Product (V) is a mixture of the (Z) and (E)                                    (cis and trans, respectively) isomers which                                    may be separated by chromatography. The (E)                                    to (Z) ratio usually is substantially higher                                   with Alternative b than with Alternative a,                                    the former usually yielding only a very small                                  quantity of the (Z) isomer.                                             B (Deprotec-                                                                          1-4 moles, pref. 2-4 moles, fluoride reagent,                                                          20°-60° C.,                                                                2-30 hrs.                                                                             AIO, e.g.,                                                                               --,                  tion)  esp. tetra- -n-butylammonium fluoride, per                                                             20°-25° C.                                                                        pref. THF                             mole V and 1-2 moles, pref. 1.2-1.5 moles,                                     glacial acetic acid per mole fluoride                                          reagent. First add glacial acetic acid to                                      solution of V, then add fluoride reagent.                               C (Hydro-                                                                             Excess hydrogen (more than 1 mole per mole V)                                                          20°-25° C.                                                                 Until 1                                                                               Lower alkanol,                                                                           --                   genation)                                                                             and catalytic amount of platinum dioxide                                                                         mole   e.g., ethanol                         (e.g., 1-5 g. per mole V). Initial hydrogen                                                                      hydrogen                                     pressure is conveniently 30-60 p.s.i.                                                                            per mole V                                                                     is taken up                           D (Deprotec-                                                                          Same as Reaction B (Molar quantities are                                                               Same as B Same as B                                                                             Same as B --                   tion)  per mole VII).                                                          E (Wittig)                                                                            Same as Reaction A. (Reactant in Step 2                                                                Same as A Same as A                                                                             Same as A Yes                         is X.) Product (XI) is a mixture of the                                        (Z) and (E) (cis and trans, respectively)                                      isomers which may be separated by                                              chromatograpy. The (E) to (Z) ratio is                                         usually substantially higher with Alternative                                  b then with Alternative a, the former usually                                  yielding only a very small quantity of the                                     (Z) isomer.                                                             F (Deprotec-                                                                          Same as Reaction B except utilize 2-8 moles,                                                           Same as B Same as B                                                                             Same as B --                   tion)  pref. 4-8 moles, fluoride reagent per mole                                     XI.                                                                     G (Hydro-                                                                             Same as Reaction C (Molar quantities are                                                               Same as C Same as C                                                                             Same as C --                   genation)                                                                             per mole XI).                                                           H (Deprotec-                                                                          Same as Reaction B except utilize 2-8 moles,                                                           Same as B Same as B                                                                             Same as B --                   tion)  pref. 4-8 moles, fluoride reagent per mole                                     XIII.                                                                   I      (1)                                                                              Generation of dianion of XVI: 1 mole                                                                 -50°-10° C.,                                                               0.5-3 hrs.                                                                            AIO, e.g.,                                                                               Yes                           XVI and 2-2.4 equivalents strong base,                                                               pref. -20°-5° C.                                                                  pref. THF                               pref. 1-1.1 moles sodium hydride then                                          1-1.1 moles  -n-butyllithium or 2-2.2 moles                                    lithium diisopropylamide.                                                    (2)                                                                              1-2.5 moles, pref. 1.2-2.2 moles, more                                                               -80°-0° C.,                                                                0.3-4 hrs.,                                                                           Same as Step                                                                             Yes                           pref. 1.3-2 moles, dianion of XVI                                                                    -50°-0° C.,                                                                pref. 0.3                                      (assuming 100% conversion of XVI to its                                                              pref. -30°-                                                                       1.5 hrs.                                       dianion) per mole XV. Product (XVII)                                                                 -10° C.                                           is racemic.                                                                  (3)                                                                              Quench with, e.g., saturated aqueous                                                                 Same as Step 2                                                                           1-5 min.                                                                              Same as Step                                                                             --                            ammonium chloride solution.                                           J (Reduction)                                                                         (a)                                                                              Non-stereoselective:                                                           1-4, pref. 2-4, equivalents transferable                                                             -10°-30° C.                                                                1-8 hrs.                                                                              IO, e.g., Yes                           hydride per mole XVII, pref. sodium    lower alkanol,                          borohydride or complex of  .sub.-t-butylamine and                                                                     esp. ethanol                            borane. When a racemic XVII is utilized,                                       product (XVIII) is a mixture of all four                                       possible stereoisomers (the erythro and                                        threo racemates) wherein the ratio of the                                      erythro stereoisomers to the threo stereo-                                     isomers is about 3:2-2:3.                                                    (b)                                                                              Stereoselective:                                                               (1)                                                                              1-2 moles, pref. 1.02-2 moles, tri-                                                                0°-50° C.,                                                                 0.5-6 hrs.,                                                                           AIO, pref.                                                                               --,                             (primary or secondary C.sub.2-4 alkyl)-                                                            0°-25° C.                                                                  pref. 1-3.5                                                                           esp. THF, or                              borane, pref. triethylborane or tri- -n-                                                                     hrs.   pref., mixture                            butylborane, and, optionally, 0.5-8  of THF and                                liters, e.g., 0.75-6.5 liters, air (at                                                                              methanol, more                            25° C. and 760 mm. Hg) per mole XVII.                                                                        pref., a 3-4:1                                                                 mixture                                 (2)                                                                              0.4-10 moles, pref. 1-10 moles, sodium                                                             -100°--20° C.,                                                             2-96 hrs.,                                                                            Same as Step                                                                             --                              borohydride per mole XVII. After the                                                               pref. -90°-                                                                       pref. 12-72                                      reaction, quench reaction mixture                                                                  -70° C.                                                                           hrs.                                             with, for example, 10% hydrochloric                                            acid and isolate crude product                                                 by extracting with a suitable inert                                            organic solvent (e.g., diethyl ether)                                          and evaporating the solvent at reduced                                         pressure. It is pref. to crystallize                                           the cyclic boron ester, if possible.                                         (3)                                                                              Large excess of anhydrous methanol,                                                                20°-40° C.                                                                 0.7-5 hrs.,                                                                           Neat      --                              e.g., 50-100 moles per mole XVII.                                                                            pref. 2-4                                                                      hrs.                                         (c)                                                                              Alternative stereoselective:                                                   (p)                                                                              Preparation of zinc borohydride/diethyl                                                            20°-25° C.                                                                 16-18 hrs.                                                                            Anhydrous Yes                             ether: Add 1 mole zinc chloride      diethyl ether                             to 5 1. anhydrous diethyl ether                                                followed by 2 moles sodium borohydride.                                        Stir for 16-18 hrs. and decant off the                                         solution (a 0.15-0.2 M. solution of                                            zinc borohydride in diethyl ether).                                            N.B. The solid should be decomposed                                            very carefully.                                                              (1)                                                                              1-6 moles zinc borohydride (in form                                                                -80°--50° C.,                                                              0.5-5 hrs.,                                                                           AIO, pref.                                                                               Yes                             of solution produced in Step p) per                                                                pref. -80°-                                                                       pref. 1-2                                                                             esp. diethyl                              mole XVII.          -60° C.                                                                           hrs.   ether or mix-                                                                  ture of diethyl                                                                ether with                                                                     another ES                              (2)                                                                              Add excess methanol, e.g., 10-100                                                                  -80°-25° C.,                                                               1-2 hrs.                                                                              Same as Step                                                                             --                              moles per mole XVII.                                                                               pref. -80°-                                                             -75° C. →                                                        20°-25° C.                                 (3)                                                                              Add water or excess dilute aqueous                                                                 -80°-25° C.                                                                --     Same as Step                                                                             --                              acetic acid to quench the reaction                                                                 NOTE: Warming                                              mixture or water followed by dilute                                                                to 20°-25° C. can                            aqueous acetic acid.                                                                               be done after                                                                  addition of                                                                    methanol, water                                                                or dilute                                                                      aqueous acetic                                                                 acid                                                   When a racemic XVII is utilized in                                             Alternative b or c, product (XVIII) is a                                       mixture of the four possible stereoisomers                                     wherein the ratio of the erythro isomers                                       (racemate) to the threo isomers (racemate)                                     is about 2-20:1, usually 5-15:1. Repeat-                                       ed recrystallization of the cyclic boron                                       ester produced in Step 2 of Alternative b,                                     if a solid, may raise the ratio or even yield                                  pure erythro racemate and mother liquors                                       enriched with the threo racemate. When,                                        however, the solvent in Step 1 of Alternative                                  b is a mixture of THF and methanol, said                                       ratio may be as high as 50-100:1.                                       K      (1)                                                                              Generation of monoanion of XIX: 1-1.1                                                                -80°--40° C.,                                                              0.25-1.5                                                                              AIO, e.g.,                                                                               Yes                           equivalents strong base, pref. lithium                                                               pref. -80°-                                                                       hrs.   pref. THF                               diisopropylamide, per mole XIX.                                                                      -75° C.                                         (2)                                                                              1-4 moles, pref. 3 moles, monoanion of XIX                                                           -80°--40° C.,                                                              0.25-1.5                                                                              Same as Step                                                                             Yes                           (assuming 100% conversion of XIX to its                                                              pref. -80°-                                                                       hrs.                                           monoanion) per mole XV.                                                                              -75° C.                                         (3)                                                                              Quench with, for example, saturated                                                                  -80°-25° C.                                                                1-5 min.                                                                              --        --                            aqueous ammonium chloride solution.                                          Product (XX) is a racemate.                                             L (Acylation)                                                                         1-3 moles, pref. 2 moles, XXI or XXII per                                                              -10°-50° C.,                                                               2-18 hrs.,                                                                            Pyridine                                                                                 Yes                         mole XX. When an ES is used as the solvent,                                                            pref. 20°-30° C.                                                           pref. 4-12                                                                            anhydrous ES,                         also use 1-4 moles, pref. 2.5-3 moles, of a                                                                      hrs.   pref. THF                             tertiary amine, e.g., pyridine or, pref.,                                      4-dimethylaminopyridine, per mole XX.                                   M      (1)                                                                              Generation of monoanion of XXIV: 1-1.1                                                               -80°-0° C.                                                                  0.25-1 hr.                                                                           AIO, e.g.,                                                                               Yes                           equivalents strong base, pref. lithium pref. THF                               diisopropylamide, per mole XXIV.                                             (2)                                                                              1-4 moles, pref. 3 moles, monoanion of                                                               -80°--40° C.,                                                              0.25-1.5                                                                              Same as Step                                                                             Yes                           XXIV (assuming 100% conversion of XXIV to                                                            pref. -80°-                                                                       hrs.                                           its monoanion) per mole XXIII.                                                                       -70° C.                                         (3)                                                                              Quench with, for example, saturated                                                                  -80°-25° C.                                                                1-5 min.                                                                              --        --                            aqueous ammonium chloride solution.                                   N      1-1.1 equivalents XXVI per mole of ester                                                               0° C.-reflux,                                                                     1-4 hrs.                                                                              Inert aqueous                                                                            --                   (Hydrolysis)                                                                          group to be hydrolyzed. To obtain a                                                                    pref. 0°-75° C.,                                                                  organic, e.g.,                        product (XXVII) containing one or more                                                                 esp. 20°-50° C.                                                                   mixture of                            --COOR.sub.18 groups, utilize 1 or less than 1                                                         when all ester   water and lower                       equivalent XXVI per mole of ester group to be                                                          groups are to    alkanol, pref.                        hydrolyzed and separate the desired                                                                    be hydrolyzed    mixture of                            product(s) from the resulting mixture.                                                                 and 0°-25° C.                                                                     water and                                                     otherwise        methanol or,                                                                   esp., ethanol                  AA     1-1.3 equivalents XXVI per mole of ester                                                               0° C.-reflux,                                                                     1-4 hrs.                                                                              Inert aqueous                                                                            --                   (Hydrolysis)                                                                          group to be hydrolyzed. To obtain a product                                                            pref. 0°-75° C.,                                                                  organic, e.g.,                        (XXIX or XXX) containing one or more ester                                                             esp. 20°-70° C.                                                                   mixture of                            groups and/or if it is desired to isolate                                                              when all ester   water and lower                       XXIX or XXX, utilize 1 or less than 1 equiva-                                                          groups are to be alkanol, pref.                        lent, e.g., 0.93-0.99 equivalent, XXVI per                                                             hydrolyzed and   mixture of                            mole of ester group to be hydrolyzed and                                                               0°-25° C. other-                                                                  water and                             separate the desired product(s) from the                                                               wise             methanol or,                          resulting mixture if a mixture is obtained.                                                                             esp., ethanol                  AB     1 equivalent acid, e.g., 2N. hydrochloric                                                              0°-25° C.,                                                                 1-5 min.                                                                              Water or                                                                                 --x-                 (Acidifica-                                                                           acid, per mole of --COO.sup.⊖  M.sub.2.sup.⊕ group to              be                      0°-15° C. when                                                                    ture of water                  tion)  acidified.              one or more      and water-                                                    --COOR.sub.18 groups                                                                            miscible inert                                                are present      organic sol-                                                                   vent, e.g.,                                                                    methanol,                                                                      ethanol,                                                                       diethyl ether                                                                  or THF                         AC     0.95-1 equivalent, pref. 0.96-0.98                                                                     0°-25° C.,                                                                 2-10 min.                                                                             Same as                                                                                  --                   (Neutraliza-                                                                          equivalent, XXXII per mole of carboxy group                                                            20°-25° C. when                   tion)  to be neutralized and separate the desired                                                             no --COOR.sub.18                                       product(s) from the resulting mixture if a                                                             group is present                                       mixture is obtained.    and otherwise                                                                  0°-15° C.                         AD     Alternative a:                                                          (Lactoniza-                                                                           Use of catalytic amount of strong acid                                                                 75° C.-reflux,                                                                    3-18 hrs.,                                                                            AIO, pref.                                                                               --,                  tion)  such as  -p-toluenesulfonic acid monohydrate                                                           pref. 75°-                                                                        pref. 4-7                                                                             e.g., benzene,                        is optional but usually omit. Use of                                                                   150° C., esp.                                                                     hrs.   toluene or                            Dean-Stark apparatus is pref. if solvent                                                               80°-120° C.                                                                       xylene or                             forms azeotrope with water.              mixture                                                                        thereof                               Alternative b:                                                                 1-1.5 moles of a lactonization agent,                                                                  10°-35° C.,                                                                2-8 hrs.,                                                                             AIO, pref.                                                                               --                          e.g., a carbodiimide, pref. a water-                                                                   20°-25° C.                                                                 pref. 3-4                                                                             HLA, esp.                             soluble carbodiimide such as N--cyclo-                                                                           hrs.   methylene                             hexyl-N'--[2'-(N"--methylmorpholinium)-  chloride                              ethyl]carbodiimide  -p-toluenesulfonate,                                       per mole XXXI.                                                                 When ImD contains one or more carboxy groups,                                  run reaction in relatively dilute solution                                     to minimize formation of undesired by-                                         products. Alternative b often results in                                       higher yields of XXXV than Alternative a.                                      Racemic erythro XXXI yields racemic trans                                      (lactone) XXXV, racemic threo XXXI yields                                      racemic cis (lactone) XXXV, mixture of                                         racemic erythro and threo XXXI yields mixture                                  of racemic trans and cis (lactones) XXXV,                                      and single enantiomer of XXXI yields single                                    enantiomer of XXXV, e.g., 3R,5S erythro XXXV                                   yields 4R,6S trans XXXV.                                                AE     0.95-1 equivalent, pref. 0.96-0.98 equiva-                                                             0°-25° C.,                                                                 2-10 min.                                                                             Same as                                                                                  --                   (Neutraliza-                                                                          lent, XXXII per mole of carboxy group to be                                                            0°-15°  C.                        tion)  neutralized and separate the desired                                           product(s) from the resulting mixture if a                                     mixture is obtained.                                                    AF     1-1.3 equivalents or, if it is desired to                                                              0° C.-reflux,                                                                     1-6 hrs.,                                                                             Same as AA                     (Hydrolysis)                                                                          isolate XXXVII and/or if ImD contains one or                                                           pref. 0°-75° C.,                                                           pref. 1-4                                    more --COOR.sub.18 groups not to be hydrolyzed,                                                        more pref. 20°-                                                                   hrs.                                         0.95-1 equivalent, pref. 0.97-0.99                                                                     75° C., esp. 40°-                        equivalent, XXVI per mole XXXV plus, in each                                                           60°C.                                           case, 1-1.05 equivalents or, if it is desir-                                   ed to isolate XXXVII and/or if ImD contains                                    one or more --COOR.sub.18 groups not to be hydro-                              lyzed, 0.95-1 equivalent, pref. 0.97-0.99                                      equivalent, XXVI per mole of carboxy group                                     and --COOR.sub.18 group to be hydrolyzed and                                   separate the desired product(s) from the                                       resulting mixture if a mixture is obtained.                                    Racemic trans (lactone) XXXV yields racemic                                    erythro XXXVII, racemic cis (lactone) XXXV                                     yields racemic threo XXXVII, mixture of                                        racemic trans and cis (lactones) XXXV yields                                   mixture of racemic erythro and three XXXVII,                                   and single enantiomer of XXXV yields single                                    enantiomer of XXXVII, e.g., 4R,6S trans                                        XXXV yields 3R,5S erythro XXXVII.                                       AG     At least 2 moles, e.g., 2-10 moles, pref.                                                              0°-70° C.,                                                                 2-12 hrs.                                                                             AIO, e.g.,                                                                               --                   (Esterifica-                                                                          2.05-2.5 moles, XXXVII per mole XXXV plus, in                                                          20°-25° C.                                                                        such as THF or                 tion)  each case, 1 mole XXXVII per mole of carboxy                                                                            alcohol of the                        group (in ImD) and separate the desired  formula R.sub.16 --OH                 product(s) from the resulting mixture if a                                                                              (R.sub.16 same as                     mixture is obtained.                     in XXXVII), if                        Racemic trans lactone XXXV yields racemic                                                                               as liquid                             erythro XXXVIII, racemic cis (lactone)                                         XXXV yields racemic threo XXXVIII, mixture of                                  racemic trans and cis (lactones) XXXV yields                                   mixture of racemic erythro and threo                                           XXXVIII, and single enantiomer of XXXV                                         yields single enantiomer of XXXVIII, e.g.,                                     4R,6S trans XXXV yields 3R,5S erythro                                          XXXVIII.                                                                AH (Ion                                                                               utilize an ion exchange resin such as                                                                  20°-25° C.                                                                 --     --        --                   Exchange)                                                                             Amberlite IR-P64 having the desired M.sup.⊖  ions                      by the conventional procedure, e.g., dis-                                      solve XXXVIII in water, load onto ion ex-                                      change resin column and elute the product(s)                                   with appropriate buffer.                                                AI (Acidifica-                                                                        Same as Reaction AB     Same as AB                                                                               Same as AB                                                                            Same as                                                                                  --                   tion)                                                                          AJ     Same as Reaction AC     Same as AC                                                                               Same as AC                                                                            Same as                                                                                  --                   (Neutrali-                                                                     zation)                                                                        AK     1 equivalent XLII per mole XXXI. If XLII is                                                            0°-25° C.,                                                                 1-15 min.,                                                                            IO, pref.                                                                                --wer                (Acidifica-                                                                           a gas such as hydrogen chloride, can bubble                                                            20°-25° C.                                                                 pref. 1-5                                                                             alkanol, e.g.,                 tion)  excess XLII through solution of XXXI. Can                                                                        min.   methanol or                           start with XXIX, XXXIII, XXXIV, etc. and ethanol, or ES,                       synthesize XXXI by or analogously to     e.g., diethyl                         Reaction AB.                             ether, water or                                                                mixture of                                                                     water and IO                   AL     Same as Reaction AK (Molar quantities are per                                                          Same as AK                                                                               Same as AK                                                                            Same as                                                                                  --                   (Acidifica-                                                                           mole XLIV). Can start with XXX, XXXVIII,                                tion)  XLI, etc. and synthesize XLIV by or                                            analogously to Reaction AI.                                             AM     Same as Reaction AK (Molar quantities are per                                                          Same as AK                                                                               Same as AK                                                                            Same as                                                                                  --                   (Acidifica-                                                                           mole XXXV). Can start with XXXVI and                                    tion)  synthesize XXXV analogously to Reactions AB                                    and AI.                                                                 BA     (a)                                                                              When X.sub.7 is --CH═CH-- or --CH.sub.2 --CH═CH--:            (Oxidation)                                                                             5-50 moles manganese dioxide (pref.                                                                  20°-80° C.,                                                                1-4 days                                                                              AIO, pref.                                                                               Yes                           activated) per mole XLVII.                                                                           40°-80° C.                                                                        or HC, esp.                                                                    toluene                               (b)                                                                              When X.sub.7 is --(CH.sub.2).sub.m -- or --CH═CH--CH.sub.2                 --:                                                                            (1)                                                                              Preparation of Swern's Reagent: 0.9596                                                             -20°-0° C.                                                                 5-15 min.                                                                             Neat      Yes                             1. oxalyl chloride and 1.561 1.                                                dimethyl sulfoxide per mole XLVII to be                                        used in Step 2.                                                              (2)                                                                              Swern's Reagent from Step 1 and 6.969                                                              -60°-40° C.,                                                               1-6 hrs.                                                                              Methylene Yes                             1. triethylamine per mole XLVII.                                                                   pref. -50° C.                                                                            chloride                       BB     Same as Reaction AA     Same as AA                                                                               Same as AA                                                                            Same as                                                                                  --                   (Hydrolysis)                                                                   BC     Same as Reaction AB     Same as AB                                                                               Same as AB                                                                            Same as                                                                                  --                   (Acidifica-                                                                    tion)                                                                          BD     Same as Reaction AK (Molar quantities are per                                                          Same as AK                                                                               Same as AK                                                                            Same as                                                                                  --                   (Acidifica-                                                                           mole LI). Can start with XLIX or LIII and                               tion)  synthesize LI by or analogously to Reaction                                    BC.                                                                     BE     Same as Reaction AC     Same as AC                                                                               Same as AC                                                                            Same as                                                                                  --                   (Neutraliza-                                                                   tion)                                                                          BF     1-5 moles LV and catalytic amount of acid,                                                             20°-40° C.                                                                 1-6 hrs.                                                                              AIO, e.g.,                                                                               --                   (Esterifica-                                                                          e.g.,  -p-toluenesulfonic acid monohydrate, per                                                                         such as THF or                 tion)  mole LI. When reaction is run neat, use  neat (if LV                           large excess of LV, e.g., 50-100 moles, per                                                                             is a liquid)                          mole LI. When ImD contains one or more                                         carboxy groups not to be esterified, use                                       0.9-1 mole LV per mole LI and separate the                                     desired product from the resulting mixture.                             BG     Same as Reaction AK (Molar quantities are per                                                          Same as AK                                                                               Same as AK                                                                            Same as                                                                                  --                   (Acidifica-                                                                           mole LVI). Can start with L, LVIII, etc. and                            tion)  synthesize LVI by or analogously to Reaction                                   BC.                                                                     BH     Same as Reaction AC     Same as AC                                                                               Same as AC                                                                            Same as                                                                                  --                   (Neutrali-                                                                     zation)                                                                        BI (Ketaliza-                                                                         (a)                                                                              When each R.sub.15 is C.sub.1-6 alkyl not containing                  tion)    an asymmetric carbon atom:                                                     3-5 moles LX and catalytic amount of                                                                 20°-25° C.                                                                 24-72 hrs.                                                                            AIO, e.g.,                                                                               Yes                           pyridinium  -p-toluenesulfonate per mole                                                                              or HC, esp.                             LIX.                                   methylene                                                                      chloride or                                                                    benzene                               (b)                                                                              When the two R.sub.15 's taken together are                                    --(CH.sub.2).sub.q --:                                                         2-3 moles LXI and catalytic amount                                                                   20°-25° C.                                                                 24-72 hrs.                                                                            Same as   Yes                           (e.g., 1-3 g) of pyridinium            Alternative a                            -p-toluenesulfonate per mole LIX.                                    BJ (Hydroly-                                                                          Same as Reaction AA     Same as AA                                                                               Same as AA                                                                            Same as                                                                                  --                   sis)                                                                           BK (Ion Ex-                                                                           Same as Reaction AH     Same as AH                                                                               Same as AH                                                                            Same as                                                                                  --                   change)                                                                        BL (Ion Ex-                                                                           Same as Reaction AH     Same as AH                                                                               Same as AH                                                                            Same as                                                                                  --                   change)                                                                        CA     (a)                                                                              When R.sub.3a is other than hydrogen:                                 (Acylation)                                                                             1-1.5 moles, pref. 1.1-1.3 moles, LXIX and                                                           -5°-15° C.                                                                 1-5 hrs..                                                                             Mixture of                                                                               --,                           2-3 equivalents of a base such as sodium                                                             20°-25° C. if                                                                     pref. dioxane                           hydroxide per mole LXVIII. Simultaneously                                                            --COOR.sub.18 group is                                                                          or THF, and                             add solution of LXIX and base to basic                                                               present)         water                                   solution of LXVIII or add LXIX neat or in                                      solution to mixture of base and LXVIII.                                        Reaction mixture must be basic at all                                          times. Combine reactants at -5°-15° C.                           and then, if desired, reaction mixture                                         may be allowed to warm to 20°-25° C. if                          no ester group is present. After the                                           reaction, acidify with, for example,                                           concentrated sulfuric or hydrochloric                                          acid                                                                  CA     (b)                                                                              When R.sub.3a is hydrogen:                                            (Acylation)                                                                             2-4 moles LXX per mole LXVIII. Start                                                                 0°-10° C. →                                                         1-2 hrs.                                                                              90% formic                                                                               --id                          reaction at 0°-10° C. and after ˜40                                              20°-25° C.                                                                        or acetic acid                          reaction mixture may be allowed to warm to                                     20°-25° C. See Muramatsu et al., Bull.                           Chem. Soc. Japan 38, 244-246 (1965). See                                       Sheehan et al., J. Am. Chem. Soc. 80,                                          1154-1158 (1958) for alternate procedure.                             CB     Alternative a:                                                                 2-4 moles, pref. 3 moles, acetic                                                                       15°-140° C.,                                                               2-24 hrs.                                                                             Neat      Yes                         anhydride, 1-3 moles, pref. 2-2.2 moles,                                                               pref. 20°-30° C.                         of an organic base, pref. 2 moles of a                                         tri-(C.sub.1-3 alkyl)amine, e.g., triethyl-                                    amine, and catalytic amount, e.g., 0.1                                         mole, of 4-dimethylaminopyridine, per                                          mole LXXI. After the reaction ,reaction                                        mixture may be quenched with, for example,                                     methanol or water.                                                             Alternative b:                                                                 (1)                                                                              2-6 moles, pref. 3-5 moles, acetic                                                                   20°-25° C.                                                                 0.5-1.5                                                                               Neat      Yes                           anhydride, 4-6 moles of an organic base,                                                                       hrs.                                           pref. pyridine, and catalytic amount,                                          e.g., 0.005-0.1 mole, of 4-dimethylamino-                                      pyridine per mole LXXI.                                                      (2)                                                                              Add solvent and heat. 100°-130° C.                                                               2-4 hrs.                                                                              Glacial                                                                                  Yestic                                                               acid                           CC     Alternative a:                                                                 1-moles LXXIII and catalytic amount                                                                    80°  C.-reflux,                                                                   18-72 hrs.                                                                            AIO, pref.                                                                               Yes                         (e.g., 0.1-5 g.) of  -p-toluenesulfonic acid                                                           pref. 100°-                                                                              e.g., benzene                         monohydrate per mole LXXII. Pref. use                                                                  111° C.   or toluene                            Dean-Stark apparatus if solvent forms                                          azeotrope with water. - Alternative b:                                         10-20 moles LXXIII, 30-50 moles of a de-                                                               20°-40° C.                                                                 4-6 days                                                                              AIO, pref.                                                                               Yes-                        hydrating agent such as magnesium sulfate                                                                               ture of HLA                           and catalytic amount (e.g., 0.5-5 g.) of and HC, esp.                           -p-toluenesulfonic acid monohydrate per mixture of                            mole LXXII.                              methylene                                                                      chloride and                                                                   benzene                        CD     1.5-3 moles, pref. 1.9-2.1 moles, phosphorus                                                           -30°-30° C.                                                                2-72 hrs.                                                                             HLA, pref.                                                                               Yes                         pentachloride per mole LXXIV. Combine                                                                  → 20°-55° C.                                                               chloroform or                         reactants at -30°-30° C. and maintain                                                                     methylene                             20°-55° C. for balance of reaction                                                                        chloride, or                          Quench reaction mixture at 0°-30° C.                                                                      mixture of HC                         water and then make basic with, for example,                                                                            and HLA, pref.                        10-50% sodium hydroxide solution or quench                                                                              mixture of                            with aqueous base, e.g., mixture of ice and                                                                             toluene and                           sodium hydroxide solution.               methylene                                                                      chloride                       CE     1-2.1 moles lead tetraacetate and, pref.,                                                              20°-80° C.                                                                 1.5-16 hrs.                                                                           Glacial                                                                                  --etic                      catalytic amount (e.g., 0.5-2 g.) of benzoyl                                                                            acid or HC such                       peroxide per mole LXXV. Generally, use of                                                                               as benzene                            benzoyl peroxide and glacial acetic acid                                       permits use of reaction times at lower end                                     of the indicated range; the reaction                                           temperature must usually be at least 50° C.                             when no benzoyl peroxide is used.                                       CF     1-6 equivalents or, when ImA contains one or                                                           0°-50° C.,                                                                 2-24 hrs.                                                                             Same as                                                                                  --                   (Hydrolysis)                                                                          more --COOR.sub.18 groups, 0.95-1 equivalent of a                                                      0°-5° C. when ImA                        base, pref. sodium hydroxide or potassium                                                              contains one or                                        hydroxide, per mole LXXVI and, if a mixture                                                            more --COOR.sub.18                                     is obtained, separate the desired product                                                              groups and                                             from the mixture.       otherwise                                                                      20°-50° C.                        CG     5-60 moles, pref. 10-40 moles, manganese                                                               20° C.-reflux,                                                                    1 hr. - 9                                                                             AIO, pref.                                                                               Yes with             (Oxidation)                                                                           dioxide, pref. activated manganese dioxide,                                                            pref. reflux,                                                                            days, pref.                                                                           or ES, esp.                                                                              N--                         or 2-4 moles N--methylmorpholine-N--oxide                                                              esp. refluxing                                                                           1-16 hrs.                                                                             toluene,  methyl-                     monohydrate and catalytic amount (e.g.,                                                                toluene with                                                                             in reflux-                                                                            diethyl                                                                                  morpho-                     0.02-0.05 mole) of ((C.sub.6 H.sub.5).sub.3 P).sub.3 RuCl.sub.2                (tris-                  manganese ing    or THF or                                                                                line                        (triphenylphosphine)ruthenium(II) chloride)                                                            dioxide and                                                                              toluene,                                                                              ture of                                                                                  N--oxide                    per mole LXXVII.        20°-25° C.                                                                 with   ether and                                                                                mono-                                               N--methyl-                                                                               manganese                                                                             with manganese                                                                           hydrate                                             morpholine N--                                                                           dioxide and                                                                           dioxide and dry                                               oxide mono-                                                                              pref. 10-                                                                             acetone with                                                  hydrate   18 hrs.                                                                               N--methylmorpho-                                                        with N--                                                                              line-N--oxide                                                           methylmor-                                                                            monohydrate                                                             pholine-N--                                                                    oxide mono-                                                                    hydrate                               CH (Wittig)                                                                           (1)                                                                              Synthesis of ylide: 1-1.05 moles strong                                                              -40°-0° C.,                                                                1-4 hrs.                                                                              AIO, pref.                                                                               Yes                           base, e.g., sodium hydride, phenyllithium                                                            pref. -35°-                                                                              e.g., THF                               or, pref.  -n-butyllithium per mole LXXIX.                                                           -20° C.                                           Pref., slowly add solution of strong                                           base to solution of LXXIX.                                                   (2)                                                                              Synthesis of enol ether: Ylide from                                                                  -30°-0° C.,                                                                1-4 hrs.                                                                              Same as Step                                                                             Yes                           1-1.05 moles LXXIX per mole LXXVIII.                                                                 pref. -20°-0° C.                         (3)                                                                              Hydrolysis of enol ether: Large molar                                                                0°-30° C.                                                                  8-24 hrs                                                                              Mixture                                                                                  --                            excess, e.g., 2-20 moles, strong acid, aqueous acid                            e.g., 70% perchloric acid, per mole    and ES, e.g.,                           LXXVIII used in Step 2.                mixture of 70%                                                                 perchloric                                                                     acid and THF                   CI (Wittig)                                                                           Same as Reaction CH (Molar quantities in                                                               Same as CH                                                                               Same as CH                                                                            Same as                                                                                  Same as                     Steps 2 and 3 are per mole LXXX).                  CH                   CJ (Wittig)                                                                           Same as Reaction CH (Molar quantities in                                                               Same as CH                                                                               Same as CH                                                                            Same as                                                                                  Same as                     Steps 2 and 3 are per mole LXXXI).                 CH                   CK (Wittig)                                                                           Alternative a:                                                                 1-2 moles, pref. 1.1-1.7 moles, LXXXIII                                                                80°  C.-reflux,                                                                   6-18 hrs.                                                                             AIO, pref.                                                                               Yes                         per mole LXXVIII.       esp. refluxing   esp. toluene                                                  toluene                                                Alternative b:                                                                 (1)                                                                              Synthesis of ylide: 1-1.08 moles strong                                                              -20°-25° C.,                                                               1-2 hrs.                                                                              AIO, pref.                                                                               Yes                           base, pref. sodium hydride, per mole                                                                 pref. -20°-0° C.                                                                  esp. THF                                LXXXIV. If necessary to inititate the                                          reaction, add small amount of LXXXIV to                                        suspension of sodium hydride in THF                                            stirred at 20°-25° C., cool to -20°-0.degree              . C.                                                                           once the reaction commences and complete                                       the addition and reaction at -20°-0° C.                        (2)                                                                              1-1.25 moles ylide from LXXXIV (assuming                                                             - 20°-25° C.                                                               3-18 hrs.                                                                             Same as Step                                                                             Yes                           100% conversion of LXXXIV to ylide) per                                        mole LXXVIII. Add solution of LXXVIII to                                       ylide solution at -20°-0° C., allow to                           warm to 20°-25° C. and stir at this                              temperature for balance of reaction time.                                    (3)                                                                              Quench with, for example, saturated                                                                  -20°-25° C.                                                                1-5 min.                                                                              --        --                            aqueous ammonium chloride solution.                                   Cl     (1)                                                                              At least 2 equivalents of transferable                                                                -10°-25° C.                                                               0.7-4 hrs.,                                                                           AIO, pref.                                                                               Yes                  (Reduction)                                                                             hydride from a metal hydride reducing                                                                pref. -10°-20° C.                                                          pref. 2-3                                                                             e.g., THF, or                           agent, e.g., lithium aluminum hydride or                                                                       hrs.   mixture of THF                          diisobutylaluminum hydride, per mole   and toluene or                          LXXXV, pref. 3.8-6 moles diisobutyl-   hexane                                  aluminum hydride per mole LXXXV. When                                          ImA contains one or more --COOR.sub.18 groups,                                 use just 2 equivalents of transferable                                         hydride per mole LXXXV and separate the                                        desired product from the resulting                                             mixture (after Step 2).                                                      (2)                                                                              Quench with, for example, water or                                                                   0°-25° C.                                                                  1-5 min.                                                                              Same as Step                                                                             --                            saturated aqueous ammonium chloride                                            solution.                                                             CM     Same as Reaction CG (Molar quantities are                                                              20°-40° C.                                                                 1-24 hrs.                                                                             Same as                                                                                  Yes                  (Oxidation)                                                                           per mole (LXXXVI).                                                      CN     2-6 moles, pref. 4 moles, potassium                                                                    75°-reflux,                                                                       0.25-2 Mixture                                                                                  --                   (Oxidation)                                                                           persulfate and 1 mole cupric sulfate,                                                                  pref. reflux                                                                             hrs., pref.                                                                           acetonitrile                          pref. cupric sulfate pentahydrate, per mole                                                                      0.4-1 hr.                                                                             and water,                            LXXV.                                    pref. a 1.67:1                                                                 mixture                        CO     Alternative a:                                                                 (p1)                                                                              Preparation of cis-1-ethoxy-2-tri- -n-                                                              50°-55° C.                                                                 5 hrs. Neat      Yes                            butylstannylethylene: 1 mole                                                                        4 hrs. and                                                ethoxyacetylene and 1 mole tri- -n-                                                                 60°-70° C. for                              butyltin hydride. Add ethoxyacetylene                                                               1 hr.                                                     to tri- -n-butyltin hydride at 50° C. over                              1 hr. period and stir at 50°-55° C. for                          3 hrs. and at 60°-70° C. for 1 hr.                            (p2)                                                                              Preparation of LXXXVIII: 1-1.08 moles                                                               -80°--75° C.                                                               1-3 hrs.,                                                                             AIO, e.g.,                                                                               Yes                             -n-butyllithium and 1 mole cis -1-ethoxy-                                                                    pref. 2                                                                               pref. THF                                2-tri- -n-butylstannylethylene. Add  -n-                                                                      hrs.                                            butyllithium solution dropwise to solu-                                        tion of stannyl compound at -78° C.                                  Alternative b:                                                                 (p)                                                                              Preparation of LXXXVIII: 2-2.1 moles,                                                                -80°--75° C.                                                               1-3 hrs.,                                                                             Same as                                                                                  --ep                          pref. 2 moles,  .sub.-t-butyllithium, pref. as                                                                 pref. 2                                                                               (p2)                                    1-2 M. solution in pentane, and 1 mole                                                                         hrs.                                           1-bromo-2-ethoxyethylene.                                             (Addition)                                                                            (1)                                                                              1-1.75 moles LXXXVIII (assuming 100%                                                                 -80°--40° C.,                                                              1-8 hrs.,                                                                             Same as                                                                                  Yesp                          yield from Step p or p2) per mole                                                                    pref. -80°-                                                                       pref. 1.5-                                                                            (p2)                                    LXXVIII. Crude enol ether product of                                                                 -60° C.                                                                           5 hrs.                                         this step may be used in next step                                             without isolation and/or purification                                          but isolation and purification of enol                                         ether intermediate may improve yield of                                        LXXXVII from next step.                                                      (2)                                                                              Catalytic amount of  -p-toluenesulfonic                                                              20°-40° C.,                                                                0.5-5 hrs.                                                                            Mixture of                                                                               --                            acid or monohydrate thereof (e.g., 0.5-                                                              20°-25° C.                                                                 pref. 0.5-                                                                            and water,                              2 g., pref. 1.2-1.8 g., per mole LXXVIII                                                                       4 hrs. pref. mixture                           used in Step 1) and water.             of THF and                                                                     water                          DA     2-8 moles thionyl chloride per mole LXXVII.                                                            0°-80° C.                                                                  2-18 hrs.                                                                             Neat      --                   (Halogena-                                                                     tion)                                                                          DB     Excess triphenylphosphine, e.g., 2-10 moles                                                            60° C.-reflux                                                                     0.5-24 hrs.                                                                           AIO, pref.                                                                               Yes                         per mole XCI.           pref. ≦150° C.                                                                    absolute                                                      esp. 75°-78° C.                                                                   ethanol                                                       (in absolute                                                                   ethanol)                                        DC     1-1.1 moles XCIV per mole XCI. Can use                                                                 20°-140° C.,                                                               6-24 hrs.,                                                                            HC, e.g., Yes                         excess XCIV as the solvent.                                                                            usually   usually                                                                               benzene or                                                    110°-140° C.                                                               10-16 hrs.                                                                            xylene or neat                                                                 (excess is                                                              solvent)                              DD     Same as Reaction J, Alternative a (Molar                                                               Same as J, a                                                                             Same as J,                                                                            Same as J,                                                                               Yes                         quantities are per mole LXXX).    a                                     DE     Same as Reaction DA (Molar quantities are                                                              Same as DA                                                                               Same as DA                                                                            Same as                                                                                  --                   (Halogena-                                                                            per mole XCV).                                                          tion)                                                                          DF     Same as Reaction DB (Molar quantities are                                                              Same as DB                                                                               Same as DB                                                                            Same as                                                                                  Yes                         per mole XCVI).                                                         DG     Same as Reaction DC (Molar quantities are                                                              Same as DC                                                                               Same as DC                                                                            Same as                                                                                  Yes                         per mole XCVI).                                                         DH     (1)                                                                              Combine 1 l. saturated aqueous ammonium                                                              20°-25° C.                                                                 --     Mixture                                                                                  Yes                           hydroxide, 1.9-2.1 moles lithium       water and HLA,                          chloride, 5.9-6.1 moles potassium      pref. methylene                         hydroxide and 1-1.02 moles benzyltriethyl-                                                                            chloride                                ammonium chloride per mole XCIX to be used                                     in Step 3. See Step 1 of Example 3.                                          (2)                                                                              Bubble in ammonia for 30 min.                                                                        0° C.                                                                             30 min.                                                                               Same as Step                                                                             Yes                         (3)                                                                              Add XCIX and additional gaseous ammonia                                                              0° C.                                                                             1 hr.  Same as Step                                                                             Yes                           portionwise over period of 1 hr.       pref. mixture                                                                  of water,                                                                      methylene                                                                      chloride and                                                                   chloroform                            (4)                                                                              Bubble in additional ammonia for 5 hrs.                                                              0° C.                                                                             5 hrs. Same as Step                                                                             Yes                         (5)                                                                              Stir.                 20°-25° C.                                                                 8-24 hrs.                                                                             Same as Step                                                                             Yes                         (6)                                                                              Acidify to pH 6.5 with, for example,                                                                 20°-25° C.                                                                 1-5 min.                                                                              Water     --                            concentrated hydrochloric acid.                                              Product (C) is racemic.                                                 __________________________________________________________________________

In the preceding table,

AIO=anhydrous inert organic solvent

ES=ether solvent, for example, diethyl ether, 1,2-diethoxyethane, 1,2-dimethoxyethane, tetrahydrofuran, dioxane and mixtures thereof

esp.=especially

HC=hydrocarbon solvent, for example, benzene, toluene, xylene and mixtures thereof

HLA=halogenated lower alkane solvent, for example, carbon tetrachloride, chloroform, 1,1-dichloroethane, 1,2-dichloroethane, methylene chloride and 1,1,2-trichloroethane, usually preferably methylene chloride

hr. (hrs.)=hour(s)

IO=inert organic solvent

min.=minutes

pref.=preferably, preferred

THF=tetrahydrofuran

Most of the molar amounts (ratios) given in the preceding table are merely exemplary and may be varied, as is evident to one of ordinary skill in the art. For example, in a reaction of two compounds one of which is readily available and one of which isn't, an excess of the readily available compound may be used to drive the reaction further towards completion (unless the use of an excess would increase the synthesis of an undesired compound).

Likewise, most of the temperature ranges given in the preceding table are merely exemplary, and it is within the ability of one of ordinary skill in the art to vary those that are not critical.

The reaction times set forth in the preceding table are also merely exemplary and may be varied. As is well-known, the reaction time is often inversely related to the reaction temperature. Generally, each reaction is monitored by, for example, thin layer chromatography and is terminated when at least one starting material is no longer present, when it appears that no more of the desired product is being formed, etc.

Conventional work-up procedures have generally been omitted from the preceding table.

As utilized in the preceding table, the term "solvent" embraces mixtures of solvents and implies that the reaction medium is a liquid at the desired reaction temperature. It should, therefore, be understood that not all of the solvents listed for a particular reaction may be utilized for the entire recited temperature range. It should also be understood that the solvent must be at least substantially inert to the reactants employed, intermediates generated and end products under the reaction conditions utilized.

The term "inert atmosphere", as utilized in the preceding table, means an atmosphere that does not react with any of the reactants, intermediates or end products or otherwise interfere with the reaction. While a carbon dioxide atmosphere is suitable for certain reactions, the inert atmosphere is usually nitrogen, helium, neon, argon or krypton, or a mixture thereof, and most often dry nitrogen to maintain anhydrous conditions. Most reactions, including those where the use of an inert atmosphere is not specified, are carried out under an inert atmosphere, usually dry nitrogen, for convenience.

In the preceding table, n-butyllithium is preferably employed as a 1.3-1.7M. solution in hexane, and lithium diisopropylamide is preferably prepared in situ from n-butyllithium and diisopropylamine.

Reactions analogous to many of the reactions of this specification are described in detail in copending application Ser. No. 06/722,288, filed by Faizulla G. Kathawala on Apr. 11, 1985 and titled Indole Analogs of Mevalonolactone and Derivatives Thereof. These reactions may be carried out analogously to the corresponding reactions of said application. Said application, particularly pages 14-26, 28-52, 65-76, 82-96, 98-102, 106, 107 and 116-122 thereof, is hereby incorporated by reference. Generally, where the reaction conditions set forth in said application differ from those set forth in this specification, the reaction conditions set forth in said application may also be utilized for the compounds of this specification.

Reactions analogous to many of the reactions of this specification are also described in U.S. Pat. No. 4,613,610. Said patent, particularly column 6, line 62--column 48, last line and column 56, line 21--column 83, line 51, which is hereby incorporated by reference. Generally, where the reaction conditions set forth in said patent differ from those set forth in this specification, the reaction conditions set forth in said patent may also be utilized for the compounds of this specification.

The product of each reaction may, if desired, be purified by conventional techniques such as recrystallization (if a solid), column chromatography, preparative thin layer chromatography, gas chromatography (if sufficiently volatile), fractional distillation under high vacuum (if sufficiently volatile) or high pressure (performance) liquid chromatography (HPLC). Often, however, the crude product of one reaction may be employed in the following reaction without purification.

Some of the reactions described above may yield mixtures of two or more products only one of which leads to the desired compound of Formula I. For example, Reaction CE may yield mixtures when, for example, at least one of R_(1a), R_(3a) and R₄ -R₁₂ is primary or secondary alkyl, particularly methyl. Any obtained mixture may be separated by conventional techniques such as those set forth in the preceding paragraph.

The reactions disclosed above may be utilized to synthesize compounds of Formula I having an R₁₄ group and one or more R₁₇ groups or no R₁₄ group and two or more R₁₇ groups wherein the R₁₄ and/or R₁₇ groups are different. However, mixtures, from which the desired compound may be isolated by conventional means, such as those set forth above, are usually obtained.

It is, however, sometimes possible to increase the selectivity in, for example, Reactions AA, BB and BJ by utilizing therein compounds wherein the R₁₆ or R'₁₆ and/or R₁₈ group(s) to be hydrolyzed differ from each such group to be retained.

It is often preferable to synthesize compounds of Formula I having two or more different R₁₄ and/or R₁₇ groups (and sometimes other compounds of Formula I) by modifying the processes set forth above. For example, one can synthesize compounds of Formulae XXVIII, XLVIII and LXII having in lieu of R₁₆ or R'₁₆ and/or one or more R₁₈ groups other ester groups that may be hydrolyzed under conditions that do not affect the R₁₆, R'₁₆ and R₁₈ groups that are present and that are stable to the reaction conditions utilized to synthesize the compounds. For example, to synthesize a compound of Formula XXIX wherein ImB contains one or more --COOR₁₈ groups and no --COO.sup.⊖ M₂.sup.⊕ groups or a compound of Formula XXIX or XXX wherein ImB or ImC, as the case may be, contains one or two --COOR₁₈ groups and one --COO.sup.⊖ M₂.sup.⊕ group or one of the former and two of the latter, one can utilize the processes set forth for the synthesis of the compounds of Formula XXVIII to synthesize a corresponding compound having, in lieu of each R'₁₆ and/or R₁₈ group to be hydrolyzed, a group that may be cleaved by conditions that do not affect the R'₁₆ and/or R₁₈ group(s) to be retained, cleave said group(s) under said conditions (rather than those of Reaction AA) and, if necessary, utilize the processes set forth above to convert one or more carboxy groups into salt form. Examples of ester groups that may be cleaved without affecting some or all of the R'₁₆ and/or R₁₈ groups present are trityl, 2,2,2-trichloroethyl and allyl. It is well within the ability of one of ordinary skill in the art to synthesize compounds corresponding to those of Formulae XXVIII, LXII, etc. but having, in lieu of one or more R₁₆, R'₁₆ and/or R₁₈ groups, groups cleavable by conditions that do not affect the R₁₆, R'₁₆ and/or R₁₈ groups and to utilize said conditions to cleave said groups.

As between Reactions CE, CF and CG, on the one hand, and Reaction CN, on the ether, Reaction CN is usually preferred, particularly when ImA contains one or more --COOR₁₈ groups, since --COOR₁₈ groups may be hydrolyzed by the reaction conditions utilized in Reaction CF. As between Reactions CK, CL and CM, on the one hand, and Reaction CO, on the other, Reaction CO is usually preferred, particularly when ImA contains one or more --COOR₁₈ groups, because --COOR₁₈ groups may be reduced by the reaction conditions utilized in Reaction CL.

The compounds of Formulae IV, X, XVI, XIX, XXI, XXII, XXIV, XXVI, XXXII, XLII, LV, LX, LXI, LXVIII-LXXI, LXXIII, LXXIX, LXXXIII, LXXXIV, LXXXVIII, XCIII and XCIX and the reagents not designated by a Roman number are known or, if unknown, may be synthesized by processes analogous to those described in the literature for similar known compounds. For example: (1) The compound of Formula IV is disclosed in World (P.C.T.) Published Patent Application No. 86/00307. See also U.S. Pat. No. 4,613,610 column 19, line 13--column 20, line 65, column 38, Reaction EA--column 41, Reaction EL and column 60, lines 15-34 of said U.S. Pat. No. 4,613,610 which is hereby incorporated by reference; U.S. Pat. No. 4,625,039, which patent, particularly column 9, line 25--column 16, line 67 is also hereby incorporated by reference and column 16, line 21--column 18, line 23 and column 31, Reaction EA--column 33, Reaction EL U.S. Pat. No. 4,668,794, which are also hereby incorporated by reference. (2) Compounds of Formula X ar also disclosed in World (P.C.T.) Published Patent Application No. 86/00307. See also column 20, line 66--column 22, line 40, column 42, Reaction FA--column 44, last line and column 70, lines 49-62 of said U.S. Pat. No. 4,613,610, which are hereby incorporated by reference, abandoned application Ser. No. 06/596,411, filed by me and Charles F. Jewell, Jr. on Apr. 3, 1984 and titled Preparation of Olefinic Compounds which application, particularly pages 16-19 thereof, is hereby incorporated by reference, and column 18, lines 24-62 and column 33, Reaction FA--column 35, Reaction FD of U.S. Pat. No. 4,668,794, which are also hereby incorporated by reference. A preferred process for the synthesis of the erythro racemate of the compound of Formula X wherein R₁₃ is hydrogen, R'₁₆ is methyl, and X₄ is a direct bond is disclosed in Kapa, Tetrahedron Letters 25, 2435-2438 (1984). The other compounds of Formula X wherein R₁₃ is hydrogen, and X₄ is a direct bond in racemic erythro form may be synthesized similarly. See also U.S. Pat. No. 4,571,428, which is also hereby incorporated by reference.

A preferred process for the synthesis of the compounds of Formula LXVIII wherein R_(1a) is R_(1r), particularly those not containing any --COOR₁₈ groups, is disclosed in Reaction Scheme VII.

As is evident to those in the art, each compound of Formula I wherein Z is a group of Formula c (including those of Formulae XLVIII-LI, LIII, LIV, LVI-LVIX, LXII-LXVI, etc.) and the pharmaceutically acceptable acid addition salts thereof, and Formulae XVII, XX and XXIII has a single center of asymmetry and, therefore, may be resolved into two optically active isomers. When a compound of Formula XVII or XXIII is converted into a compound of Formula XVIII or XXV, respectively, an additional center of asymmetry is generated. Consequently, when a racemic compound of Formula XVII or XXIII is utilized, four stereoisomers (two pairs of diastereoisomers) of the resulting compound of Formula XVIII or XXV are formed, whereas when an optically pure compound of Formula XVII or XXIII is utilized, two diastereoisomers of the compound of Formula XVIII or XXV are formed. The center of asymmetry of each compound of Formulae LXVIII, LXXI, LXXII, LXXIV, etc. may be ignored since it is destroyed in Reaction CD.

The compounds of Formula I wherein Z is a group of Formula a or b (including those of Formulae XII, XIV, XVIII, XXVII-XXXI, XXXIII-XXXVI, etc.) the pharmaceutically acceptable acid addition salts thereof, and Formulae X, XI, XIII and XXV have two centers of asymmetry and, therefore, may exist in four stereoisomeric forms. Except where the compound is formed from an optically pure precursor already having both chiral carbon atoms or where the reaction involves the use of a stereospecific reagent that gives an optically pure product, the compound is obtained as a mixture of two (if formed from an optically pure compound having one center of asymmetry) or four (if formed from a racemic compound having one center of asymmetry) stereoisomers.

The obtained mixtures of stereoisomers may be separated by conventional means. For example, diastereoisomers may be separated by fractional crystallization, column chromatography, preparative thin layer chromatography and HPLC. Each mixture of four stereoisomers of a compound of Formula XXXV may, for example, be separated by HPLC into its cis and trans (lactone) components, each of which is a racemate that may be resolved into two optically active enantiomers.

Techniques for separating a racemate into its two optically active enantiomers are known. For example, a racemic compound having a carboxylic acid group may be reacted with an optically pure organic base having at least one center of asymmetry to form a mixture of diastereoisomeric salts that may be separated by fractional crystallization, column chromatography, etc. or it may be reacted with an optically pure alcohol having at least one center of asymmetry to form a mixture of diastereoisomeric esters which may be separated by conventional techniques such as those set forth above or below. Likewise, a racemic compound having a carboxylic acid, acyl halide, ester or lactone group may be reacted with an optically pure organic base, i.e., an amine, to form a mixture of diastereoisomeric amides that may be separated by conventional means, e.g., fractional crystallization, column chromatography and/or HPLC. For example, a racemic lactone of Formula XXXV may be reacted with an excess of R-(+)-α-methylbenzylamine (or the corresponding S-(-) compound) to form a mixture of two diastereoisomeric α-methylbenzylamides which may be separated by, for example, column chromatography on a silica gel column and/or by HPLC using a Partisil column. Often it is desirable to utilize both techniques, i.e., to partially separate the diastereoisomers by column chromatography and to purify each fraction by HPLC. Typically, the α-methylbenzylamides are synthesized by reacting the racemic lactone with a large molar excess of the amine at 20°-25° C. for 16-24 hours. The reaction is run neat, with the excess amine serving as the solvent. After the reaction, the excess amine is removed by vacuum distillation at 25°-35° C. After separation, each chiral amide may be hydrolyzed to the corresponding, for example, sodium, salt by, for example, refluxing with 1.5-3, preferably 2-2.2, equivalents of a base such as sodium hydroxide for 5-25 hours in a mixture of water and ethanol. The resulting salts may be converted to the corresponding free acids, esters, lactones and other salts by conventional means such as the reactions set forth in Reaction Scheme IV. On the other hand, a racemic compound having a hydroxy group may be esterified with an optically pure carboxylic acid having at least one center of asymmetry to form a mixture of diastereoisomeric esters or it may be reacted with an optically pure trisubstituted silyl halide, e.g., (-)-α-naphthylphenylmethylchlorosilane (Sommer et al., J. Am. Chem. Soc. 80, 3271 (1958).), to form a mixture of two diastereoisomeric silyloxy compounds, which mixture may be separated by conventional techniques. For example, diastereoisomeric (-)-α-naphthylphenylmethylsilyl derivatives of a lactone of Formula XXXV may be separated on a silica column having covalently bound L-phenylglycine. After separation, the optically pure salts, amides, esters or silyloxy compounds are reconverted to the corresponding carboxy group- or hydroxy group-containing compounds with retention of optical purity. For example, the process conditions disclosed for Reactions B, D, F and H may be utilized to cleave (-)-α-naphthylphenylmethylsilyl and other silyl groups. The presence of one or more interfering groups may dictate which resolution procedure is preferred.

Since any compound of Formula I wherein Z is a group of Formula a or c wherein R₁₄ is a cation other than M may be converted into the corresponding compound wherein R₁₄ is hydrogen, M or R₁₆ by the processes of Reaction Schemes IV and V, the compounds of Formula I wherein Z is a group of Formula a or c and R₁₄ is a pharmaceutically unacceptable cation are also within the scope of this invention since they are useful as intermediates. However, such compounds are not compounds of Formula I as utilized in this specification, except where indicated to the contrary.

Also within the scope of this invention are the intermediates of Formulae II, V, VII, XI, XIII, XV, XVII, XX, XXIII, XXV, LXXXV and LXXXVI. The preferences for each variable are the same as those set forth for the compounds of Formula I, with the preferred groups of such compounds including those that correspond to Groups (xxv)-(xxviii), (xciii)-(xcvi), (clxi)-(clxiv) and (ccxxix)-(ccxxxii) (for Formulae V and VII) and Groups (i)-(xxiv), (lxix)-(xcii), (cxxxvii)-(clx) and (ccv)-(ccxxviii) for each of the other formulae) to the extent consistent therewith.

The entire specification of U.S. Pat. No. 4,668,794 columns 1-22 and column 40, line 28--column 42, line 49 especially column 1, line 1--column 6, line 39, is hereby incorporated by reference as if set forth herein in its entirety.

Besides having the utility set forth below, every compound of Formula I is useful as an intermediate in the synthesis of one or more other compounds of Formula I utilizing the reactions set forth in Reaction Schemes IV and V.

The compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in cholesterol biosynthesis, and, therefore, they are inhibitors of cholesterol biosynthesis. Their biological activity may be demonstrated in the following two tests:

Test A. In Vitro Microsomal Assay of HMG-CoA Reductase Inhibition:

200 μl. aliquots (1.08-1.50 mg./ml.) of rat liver microsomal suspensions, freshly prepared from male Sprague-Dawley rats (150-225 g. body weight), in Buffer A with 10 mmol. dithiothreitol are incubated with 10 μl. of a solution of the test substance in dimethylacetamide and assayed for HMG-CoA reductase activity as described in Ackerman et al., J. Lipid Res. 18, 408-413 (1977), the concentration of the test substance in the assay system being 0.0001-2,000 μmolar. In the assay the microsomes are the source of the HMG-CoA reductase enzyme which catalyzes the reduction of HMG-CoA to mevalonate. The assay employs a chloroform extraction to separate the product, [¹⁴ C]mevalonolactone, formed by the HMG-CoA reductase reduction of the substrate, [¹⁴ C]HMG-CoA. [³ H]mevalonolactone is added as an internal reference. Inhibition of HMG-CoA reductase is calculated from the decrease in specific activity ([¹⁴ C/³ H]mevalonate) of test groups compared to controls.

The IC₅₀ is the concentration of the test substance in the assay system calculated or observed to produce a 50% inhibition of HMG-CoA reductase activity.

Test B. In Vivo Cholesterol Biosynthesis Inhibition Test:

In vivo studies utilize male Wistar Royal Hart rats weighing 150±20 g. which have been kept for 7-10 days on an altered light cycle (6:30 A.M.-6:30 P.M. dark) housed two per cage and fed powdered Purina Rat Chow and water ad libitum. Three hours before the diurnal maximum of cholesterol synthesis at mid-dark, the rats are administered orally the test substance (e.g., 0.001-200 mg./kg. body weight) dissolved or as a suspension in 0.5% carboxymethylcellulose in a volume of 1 ml./100 g. body weight. Controls receive vehicle alone. One hour after receiving the test substance (or the vehicle alone), the rats are injected intraperitoneally with about 25 μCi/100 g. body weight of sodium [1-¹⁴ C]acetate 1-3 mCi/mmol. Two hours after mid-dark, blood samples are obtained under sodium hexobarbitol anesthesia, and the serum is separated by centrifugation.

Serum samples are saponified and neutralized, and the 3β-hydroxysterols are precipitated with digitonin basically as described in Sperry et al., J. Biol. Chem. 187, 97 (1950). The [¹⁴ C]digitonides are then counted by liquid scintillation spectrometry. After correcting for efficiencies, the results are calculated in nCi (nanocuries) of 3β-hydroxysterol formed per 100 ml. of serum. Inhibition of 3β-hydroxysterol synthesis is calculated from the reduction in the nCi of 3β-hydroxysterols formed from test groups compared to controls.

The ED₅₀ is the dose of the test substance calculated or observed to produce a 50% inhibition of 3β-hydroxysterol synthesis.

Since they inhibit cholesterol biosynthesis, the compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof (including those of each subgroup thereof) are useful for lowering the blood cholesterol level in animals, e.g., mammals, especially larger primates, in particular humans, and, therefore, as hypolipoproteinemic and anti-atherosclerotic agents.

The precise dosage of the compound of Formula I or the pharmaceutically acceptable acid addition salt thereof to be employed for inhibiting cholesterol biosynthesis depends upon several factors including the host, the nature and the severity of the condition being treated, the mode of administration and the particular active substance employed. However, in general, suitable oral daily dosages of the compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof for the satisfactory inhibition or reduction of cholesterol biosynthesis (i.e., the satisfactory reduction of the blood cholesterol level and satisfactory treatment of hyperlipoproteinemia and atherosclerosis) are indicated to 0.002-100 mg./kg. body weight, e.g., 0.002-10 mg./kg. body weight for the more active compounds. For most larger primates such as humans, a suitable oral daily dosage is indicated to be 0.1-2,000 mg., e.g., 0.1-200 mg. for the more active compounds. For administration by injection, a dosage somewhat larger lower than would be used for oral administration of the same active substance to the same host having the same condition is usually employed. However, the above dosages are also typically used for i.v. administration.

The daily dosage may be administered in a single dose but more typically is administered in two to four equal portions, typical doses being 0.025-2,000 mg. Often, a small dosage is administered initially, and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.

A typical dosage unit for oral administration may contain 0.025-500 mg. of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof.

The compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof may be formulated into conventional pharmaceutical compositions and administered by any conventional mode of administration, in particular enterally, e.g., in the form of capsules or tablets, or parenterally, e.g., in the form of sterile injectable solutions or suspensions. The pharmaceutical compositions comprise a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable solid or liquid carrier (or diluent). They may be formulated in conventional manner. The compounds and pharmaceutically acceptable acid addition salts of each subgroup thereof may likewise be formulated into such pharmaceutical compositions and administered by such routes.

The compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof (including those of each subgroup thereof) may be formulated into such pharmaceutical compositions containing an amount of the active substance that is effective for inhibiting cholesterol biosynthesis in unit dosage form and such compositions comprising at least one solid pharmaceutically acceptable carrier.

The preferred compound of this invention, that of Example 2, exhibited an IC₅₀ in Test A of 0.0026 μmolar and that of Example 10 exhibited an IC₅₀ of 0.036 μmolar in this test whereas that of Compactin was 0.94 μmolar and that of Mevinolin was 0.14 μmolar in this test. Other tested compounds of this invention exhibited IC₅₀ 's of 0.005→10 μmolar in this test. In Test B the compound of Example 2 exhibited an ED₅₀ of 0.025 mg./kg. and that of Example 10 exhibited an ED₅₀ of 0.028 mg./kg. whereas that of Compactin was 3.5 mg./kg. and that of Mevinolin was 0.41 mg./kg. Other tested compounds of this invention exhibited ED₅₀ 's of 0.045-0.26 mg./kg. in this test. The daily dosage for the compound of Example 2 is, therefore, indicated to be 0.1-50 mg., e.g., 1-20 mg., preferably 0.2-10 mg., for most larger primates such as humans. The daily dosage for the compound of Example 10 for most larger primates such as humans is indicated to be about 10% higher than that of Example 2.

Representative formulations suitable for encapsulation in a hard gelatin capsule by conventional techniques are:

    ______________________________________                                         A.  Compound of Formula I, e.g., the compound of                                                              5 mg.                                               Example 2                                                                      Corn starch                244 mg.                                             Magnesium stearate         1 mg.                                           B.  Compound of Formula I, e.g., the compound of                                                              1 mg.                                               Example 2                                                                      Corn starch                248 mg.                                             Magnesium stearate         1 mg.                                           ______________________________________                                    

The following examples show representative compounds encompassed by this invention and their synthesis. However, it should be understood that they are for purposes of illustration only.

EXAMPLE 1 Ethyl(±)-erythro-(E)-3,5-dihydroxy-7-[1'-(4"-fluorophenyl)-4'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]hept-6-enoate ##STR16## Step 1 (Reaction CA) N-Benzoyl-DL-valine (Compound CII)

119 ml. (1.025 moles) of benzoyl chloride and 760 ml. of 2N. sodium hydroxide solution (1.52 moles) are simultaneously added to a mixture of 100 g. (0.854 mole) of DL-valine, 200 ml. of dioxane and 350 ml. of 2N. sodium hydroxide solution (0.7 mole) stirred at 0°-5° C., the additions being at rates such that the pH of the reaction mixture is always basic and the temperature does not exceed 5° C., the reaction being exothermic. The reaction mixture is allowed to warm to 20°-25° C., stirred at 20°-25° C. for 2 hours, cooled to 0° C. and acidified with about 40 ml. of concentrated sulfuric acid. The precipitate is collected by filtration, washed with water, air dried for 16 hours and dissolved in ethyl acetate. The ethyl acetate solution is decanted from some residual water, and petroleum ether is added to obtain a precipitate. The precipitate is subjected to high vacuum for 8 hours to remove some residual dioxane and obtain the product (165.81 g. (88%)), m.p. 125°-128° C. Lit.: 132° C.

Revised procedure

5.1 kg. (36.28 moles) of benzoyl chloride is added portionwise to a mixture of 3.5 kg. (29.88 moles) of DL-valine, 39.0 l. of 2N. sodium hydroxide solution (78 moles) and 7 l. of tetrahydrofuran stirred at ˜10° C. at a rate such that the temperature is maintained at 10°-15° C., and the reaction mixture is warmed to ˜20° C. and stirred at ˜20° C. for 3 hours, the reaction mixture being stirred under nitrogen throughout, 1.4 l. of concentrated sulfuric acid is carefully added at a rate such that the temperature does not exceed 25° C., and the mixture is cooled to ˜5°-10° C. and stirred at this temperature for about 30 minutes to obtain a solid. (If necessary, the mixture is seeded.) The resulting solid is collected by filtration, washed three times with 20 l. portions of hot water, washed three times with 20 l. portions of hexane and dried at 40° C. and reduced pressure for ˜12 hours to obtain the product (6.4 kg.), m.p. 123°-126° C.

Step 2 (Reaction CB) (±)-N-[1-(1'-methylethyl)-2-oxopropyl]benzamide (Compound CIII)

7.4 g, (60.6 mmoles, a catalytic amount) of 4-dimethylaminopyridine is added in two portions to a mixture of 134 g. (0.606 mole) of Compound CII, 172 ml. (185.6 g., 1.818 moles) of acetic anhydride and 169 ml. (122.6 g., 1.212 moles) of triethylamine stirred at 20°-25° C. under nitrogen, and the reaction mixture is stirred at 20°-25° C. under nitrogen for 16 hours, cooled to 0°-5° C. and quenched with 350 ml. of methanol. The mixture is poured into 2 l. of ice-water, and the precipitated solid is collected by filtration, washed with about 4 l. of water and allowed to air dry for 16 hours. The resulting brown powder is recrystallized from diethyl ether, and the obtained tan needles are recrystallized from diethyl ether to obtain the product (58.83 g.), m.p. 89.5°-91.5° C. A second crop may be obtained from the combined mother liquors.

Revised procedure

402 g. (1.82 moles) of Compound CII is added rapidly to 558.3 g. (5.45 moles) of acetic anhydride stirred at 23°-25° C., 368 g. (3.64 moles) of triethylamine is added over a 6 minute period with stirring, the addition being slightly exothermic, the reaction mixture is cooled to 25° C., 22.2 g. (0.18 mole) of 4-dimethylaminopyridine is added over a period of 3 minutes with stirring at 25° C., the reaction mixture is stirred at 25°-28° C. for 2 hours with cooling because the reaction is exothermic, and the reaction mixture is stirred at 22° C. for 16 hours, the reaction mixture being stirred under nitrogen throughout. The reaction mixture is slowly added to a mixture of 3 l. of water and 3 l. of toluene stirred at 20°-25° C. at a rate such that the temperature does not exceed 28° C. The reaction vessel is rinsed with 100 ml. of toluene, and the rinse is combined with the quenched reaction mixture. The organic layer is separated, washed three times with 500 ml. portions of water and filtered through 100 g. of Celite filter aid. The Celite is washed three times with 100 ml. portions of toluene, and the washings are combined with the filtrate. Toluene is distilled at 45° C. and 20-50 mm. Hg until a thick stirrable slurry results, 250 ml. of toluene is added, the mixture is heated at 60° C. to obtain a solution, and the solution is cooled to 4° C. to obtain a yellow solid. The yellow solid is collected by filtration, washed with a cold (5° C.) mixture of 250 ml. of toluene and 250 ml. of heptane, washed with 300 ml. of cold (5° C.) heptane and vacuum dried for 16 hours at 47° C. to obtain the product (294.3 g. (73.9 %)), m.p. 90°-92° C.

Step 3 (Reaction CC) (±)-N-[2-(4'-Fluorophenyl)imino-1-(1'-methylethyl)propyl]benzamide (Compound CIV)

A mixture of 72.91 g. (332.5 mmoles) of Compound CIII, 35 ml. (40.63 g, 365.7 mmoles) of 4-fluoroaniline, a catalytic amount (50 mg.) of p-toluenesulfonic acid monohydrate and 500 ml. of dry toluene (dried over alumina) is refluxed in a Dean-Stark apparatus for 16 hours under nitrogen, the reaction mixture is allowed to cool, and the toluene is evaporated at reduced pressure to obtain the crude product as a black oil.

Revised procedure

A mixture of 500 g. (2.28 moles) of Compound CIII, 280 g. (2.52 moles) of 4-fluoroaniline, 2.5 g. (0.013 mole) of p-toluenesulfonic acid monohydrate and 5 l. of toluene is refluxed in a Dean-Stark apparatus for 20 hours under nitrogen, and the reaction mixture is cooled to -10° C. to obtain a cold solution of the crude product.

Step 4 (Reaction CD) 1-(4'-Fluorophenyl)-5-methyl-4-(1'-methylethyl)-2-phenyl-1H-imidazole (Compound CV)

A solution of crude Compound CIV from Step 3, initial procedure (332.5 mmoles assuming 100% yield) in 250 ml. of chloroform is added dropwise to a suspension of 138.5 g. (665 mmoles) of phosphorus pentachloride in 500 ml. of chloroform stirred at -20°--15° C. under nitrogen. The reaction mixture is allowed to warm to 20°-25° C. with stirring and stirred at 20°-25° C. for 16 hours, the reaction mixture being maintained under nitrogen throughout. The reaction mixture is quenched with 500 ml. of water and made basic with 10% sodium hydroxide solution. The organic phase is separated, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The obtained pale green solid is recrystallized from acetone to obtain the product as white needles (54.83 g.), m.p. 145°-148° C. A 10.83 g. second crop may be obtained from the acetone mother liquor.

Revised procedure

The cold (-10° C.) solution of crude compound CIV from Step 3, revised procedure (2.28 moles assuming 100% yield) is diluted with 4 l. of methylene chloride, the dilution being slightly exothermic. 950 g. (4.56 moles) of phosphorus pentachloride is slowly added to the solution stirred at 0° C. at a rate such that the temperature does not exceed 20°-30° C., the addition being exothermic, and the reaction mixture is heated to reflux, refluxed for 2.5 hours and cooled to -15° C., the reaction mixture being stirred under nitrogen throughout. The reaction mixture is slowly poured into a mixture of 8 kg. of ice and 1.83 kg. of 50% sodium hydroxide solution, the temperature of the mixture not being allowed to exceed 30° C. The organic layer is separated and washed with 8 l. of water. The bottom organic layer is separated and filtered, the solvent is distilled at 60° C. and 30-50 mm. Hg to obtain a thick heterogeneous mixture, and 750 ml. of acetone is added at 60° C. The mixture is cooled to 0° C. and maintained at 0° C. for 30 minutes. The resulting off-white solid is collected by filtration, washed three times with 150 ml. portions of cold (10° C.) acetone and vacuum dried at 50° C. to obtain the product (425 g. (64% (Steps 3 and 4 combined))), m.p. 146.5°- 148.5° C.

Step 5 (Reaction CE) 5-Acetoxymethyl-1-(4'-fluorophenyl)-4-(1'-methylethyl)-2-phenyl-1H-imidazole (Compound CVI)

A mixture of 21.75 g. (73.9 mmoles) of Compound CV, 65.5 g. (148 mmoles) of lead tetraacetate, 0.05 g. (0.21 mmole) of benzoyl peroxide and 500 ml. of glacial acetic acid is heated at 80° C. for 16 hours under nitrogen, cooled to 0°-5° C. and made basic (pH 8-9) with 10N. sodium hydroxide solution. The resulting suspension is filtered through a pad of Celite, the Celite is washed with water and ethyl acetate successively, and the washings are combined with the initial filtrate. The organic phase is separated, and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain the crude product as a dark brown foam (22.94 g.).

Step 6 (Reaction CF) 1-(4'-Fluorophenyl)-4-(1'-methylethyl)-2'-phenyl-1H-imidazole-5-methanol (Compound CVII)

100 ml. of 10% sodium hydroxide solution is added to a solution of 22.94 g. (≦65.1 mmoles) of crude Compound CVI from Step 5 in absolute ethanol, and the resulting reaction mixture is stirred at 20°-25° C. under nitrogen for 4 hours. The ethanol is evaporated at reduced pressure, and the resulting yellow paste is partitioned between ethyl acetate and water. The ethyl acetate phase is separated, and the aqueous phase is extracted twice with ethyl acetate. The three ethyl acetate phases are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure to a volume of about 200 ml. Petroleum ether is added to precipitate the product as a tan powder (11.54 g.). An analytical sample is recrystallized from ethyl acetate. M.p. 183°-186° C.

Step 7 (Reaction CG) 1-(4'-Fluorophenyl)-4-(1'-methylethyl)-2-phenyl-1H-imidazole-5-carboxaldehyde (Compound CVIII)

13.45 g. (43.3 mmoles) of Compound CVII is dissolved in 650 ml. of toluene with heating, 53.8 g. (619 mmoles) of activated manganese dioxide is added, and the reaction mixture is refluxed under nitrogen for 16 hours with stirring, cooled to 20°-25° C. and filtered through a pad of Celite. The Celite is washed with ethyl acetate, and the filtrate and ethyl acetate washings are combined and evaporated at reduced pressure to a tan solid. The tan solid is recrystallized from diethyl ether to obtain the product (5.12 g.). A second crop is obtained from the mother liquor by adding hexane. M.p. 159°-161° C.

Step 5A (Reaction CN) 1-(4'-Fluorophenyl)-4-(1'-methylethyl)-2-phenyl-1H-imidazole-5-carboxaldehyde (Compound CVIII)

A mixture of 5 l. of acetonitrile, 3 l. of water, 736 g. (2.72 moles) of potassium persulfate and 170 g. (0.68 mole) of copper (II) sulfate pentahydrate is heated at 65° C., 200 g. (0.68 mole) of Compound CV is added over a period of 8 minutes (the addition being slightly exothermic), and the reaction mixture is slowly heated to 75°-77° C., maintained at 75°-77° C. for 38 minutes and immediately cooled to 23° C., the reaction mixture being stirred under nitrogen throughout. The reaction solution is decanted, the solids in the reaction vessel are washed four times with 1 l. portions of methylene chloride, and the methylene chloride washings are combined with the decanted reaction solution. The aqueous layer is separated, and the organic layer is washed with 2 l. of water. The organic (bottom) layer is separated, and the solvent is distilled at a maximum external temperature of 55°-60° C. and 20-30 mm. Hg until a thick stirrable mixture results. 500 ml. of methylene chloride is added, and the mixture is heated at ˜35° C. for 5 minutes, cooled to 25° C. and filtered. The filter cake is washed twice with 50 ml. portions of methylene chloride. The methylene chloride washings are combined with the filtrate, and as much of the methylene chloride as possible is distilled at 30°-45° C. and 20-30 mm. Hg until a thick stirrable slurry results. 1.5 l. of hexane is added, and the mixture is distilled at atmospheric pressure, the vapor temperature rising from 56° C. to 67° C. as the acetonitrile is azeotroped. The atmospheric distillation is continued for ˜5 minutes after the vapor temperature rises to 67° C. to ensure complete removal of the acetonitrile, and as much of the remaining solvent as possible is distilled at ˜50° C. and 20-30 mm. Hg. The resulting thick stirrable mixture is cooled to 30° C., 1 l. of dry tetrahydrofuran and 100 g. of aluminum oxide (90 activity) are added, and the mixture is stirred for 15 minutes and filtered. The filter cake is washed three times with 200 ml. portions of dry tetrahydrofuran, and the washing are combined with the initial filtrate to obtain a solution of about 192 g. of crude Compound CVIII in 1.6 l. of tetrahydrofuran which solution may be utilized in Part (b) of either the initial procedure or the revised procedure of Step 8.

Step 8 (Reaction CK) Ethyl (E)-3-[1'-(4"-fluorophenyl)-4'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]propenoate (Compound CX)

(a) 1.8 g. of 60% sodium hydride/mineral oil (45.0 mmoles) is washed twice with hexane, the sodium hydride is suspended in 50 ml. of dry tetrahydrofuran (distilled from ketyl), the suspension is stirred at 20°-25° C., 1 ml. of triethyl phosphonoacetate (Compound CIX) is added, the reaction mixture is cooled to -20°--15° C. with stirring, 7.6 ml. of Compound CIX is added dropwise with stirring at -20°--15° C. (the total amount of Compound CIX being 8.6 ml. (9.6 g., 42.84 mmoles)), and the reaction mixture is stirred at -20°--15° C. for 1 hour to obtain a solution of the ylide, the reaction mixture being stirred under nitrogen throughout.

(b) A solution of 11.0 g. (35.7 mmoles) of Compound CVIII in 100 ml. of dry tetrahydrofuran (distilled from ketyl) is added dropwise to the ylide solution of Part (a) of this step stirred at -20°--15° C., the reaction mixture is allowed to warm to 20°--25° C. with stirring, an additional 150 ml. of dry tetrahydrofuran (distilled from ketyl) is added to dissolve the solids, and the reaction mixture is stirred at 20°-25° C. for 16 hours, the reaction mixture being maintained under nitrogen throughout. The reaction mixture is poured into water, diethyl ether, ethyl acetate and chloroform are successively added to dissolve all of the solids, the organic phase is separated, the aqueous phase is extracted with chloroform, and the organic phases are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain the product as a pale yellow powder (13.78 g.). An analytical sample is recrystallized from methylene chloride/n-hexane. M.p. 187°-189° C.

Revised procedure

(a) A solution of 76.8 ml. (396.3 mmoles) of Compound CIX in 50 ml. of dry tetrahydrofuran is added over a period of 1 hour to a mixture of 16.7 g. of 60% sodium hydride/mineral oil (417.5 mmoles) and 500 ml. of dry tetrahydrofuran (dried over 4 Å. molecular sieves) stirred at -5°-0° C., and the reaction mixture is stirred at -5°-0° C. for 1 hour, the reaction mixture being stirred under nitrogen throughout.

(b) The ylide solution from Part (a) is cooled to -5° C., a solution of 101.8 g. (330.0 mmoles) of Compound CVIII in 750 ml. of dry tetrahydrofuran is added rapidly over a 20 minute period with stirring at -5°-0° C., and the reaction mixture is allowed to warm to 20°-25° C. over a period of about 1 hour with stirring and stirred at 20°-25° C. for 2 hours, the reaction mixture being maintained under nitrogen throughout. The reaction mixture is poured into a mixture of 1.0 l. of saturated ammonium chloride solution and 1.0 l. of methylene chloride, the reaction flask is washed with 200 ml. of water and 500 ml. of methylene chloride successively, and the washings are combined with the quenched reaction mixture. The organic (lower) phase is separated, the aqueous phase is extracted with 500 ml. of methylene chloride, and the methylene chloride extract is combined with the aforementioned organic phase. The combined organic solution is washed with 500 ml. of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to a thick white slurry at 50° C. and reduced pressure. 300 ml. of acetone is added, and the mixture is similarly evaporated to a thick white slurry. 250 ml. of acetone and 150 ml. of n-heptane are added, the mixture is cooled, and the product is collected by suction filtration and vacuum dried (98.1 g.), m.p. 189°-190° C. A less pure second crop is obtained by evaporating the mother liquor at reduced pressure to about 50% of its original volume, cooling, collecting the precipitate by suction filtration and vacuum drying the precipitate (23.4 g.), m.p. 185°-187° C.

Step 9 (Reaction CL) 3-[1'-(4"-Fluorophenyl)-4'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]prop-2-en-1-ol (Compound CXI)

95.2 ml. of 1.5M. diisobutylaluminum hydride/toluene (142.8 mmoles) is added dropwise to a solution of 13.78 g. (36.4 mmoles) of Compound CX in 350 ml. of dry tetrahydrofuran (distilled from ketyl) stirred at 0° C. under nitrogen, and the reaction mixture is stirred at 0° C. under nitrogen for 45 minutes and quenched at 0° C. with saturated sodium sulfate solution. Sufficient 10% hydrochloric acid is added to dissolve the gel, and the resulting two phase mixture is extracted twice with diethyl ether. The organic phases are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness at reduced pressure to obtain the crude product as a pale yellow solid (11.42 g.). A previous batch melted at 190°-193° C. (dec.)

Revised procedure

1.268 l. of 1.0M. diisobutylaluminum hydride/hexane (1.268 moles) is added to a suspension of 120 g. (317.04 mmoles) of Compound CX in 1.0 l. of dry tetrahydrofuran (dried over 4 Å. molecular sieves) stirred at -8° C. at a rate such that the temperature of the reaction mixture does not exceed 0° C., and the resulting nearly clear yellow solution is stirred for 2.5 hours while being allowed to gradually warm to 25° C., the reaction mixture being stirred under nitrogen throughout. The reaction mixture is carefully poured into a mixture of 2.0 l. of saturated ammonium chloride solution, 500 ml. of concentrated hydrochloric acid and 2.5 kg. of ice, 1.0 l. of methylene chloride is added, sufficient 10% hydrochloric acid is added to dissolve any aluminum salts (if necessary), the organic phase is separated, and the aqueous phase is extracted three times with 1 l. portions of methylene chloride. The methylene chloride extracts are combined with the aforementioned organic phase, and the combined organic solution is washed with 1 l. of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated at 50° C. and reduced pressure to a thick slurry. 500 ml. of n-heptane is added, the mixture is cooled to 0° C., and the resulting solids are collected by suction filtration, washed twice with 200 ml. portions of heptane and vacuum dried to constant weight (2 hours) at 40° C. to obtain the crude product as a very pale yellow powder (85.4 g.), m.p. 153°-160° C. (dec.) A second crop is obtained by concentrating the mother liquor at reduced pressure to about 50% of its original volume, cooling and collecting and air drying the resulting solid (1.4 g.).

Step 10 (Reaction CM) (E)-3-[1'-(4"-Fluorophenyl)-4'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]prop-2-enal (Compound CXII)

11.4 g. (33.9 mmoles) of Compound CXI is dissolved in 250 ml. of dry tetrahydrofuran (distilled from ketyl), 29.5 g. (339 mmoles) of activated manganese dioxide is added, the reaction mixture is stirred at 20°-25° C. for about 3 hours, an additional 29.5 g. (339 mmoles) of activated manganese dioxide is added, and the reaction mixture is stirred at 20°-25° C. for 16 hours and filtered through a pad of Celite. The Celite is washed with ethyl acetate, the washing is combined with the filtrate, and the combined solution is evaporated to dryness at reduced pressure to obtain a yellow solid (10.03 g.). The yellow solid is crystallized from ethyl acetate/hexane to obtain an orange solid (6.74 g.) which is recrystallized from ethyl acetate to obtain the product as a yellow powder (4.29 g.). The mother liquors from the two crystallizations are combined, evaporated to dryness at reduced pressure and flash chromatographed on 300 g. of 230-400 mesh A.S.T.M. silica gel utilizing 30% diethyl ether/hexane as the eluant. The fractions containing the product are combined and evaporated to dryness at reduced pressure, and the residue is recrystallized from ethyl acetate/hexane to obtain additional product (3.72 g.). A previous batch melted at 163°-166° C.

Revised procedure

400 g. (4.6 moles) of activated manganese dioxide is added in one portion to a suspension of 85 g. (252.7 mmoles) of Compound CXI in 1.0 l. of dry tetrahydrofuran (dried over 4 Å. molecular sieves) stirred at 20°-25° C., the addition being slightly exothermic, and the reaction mixture is stirred at 20° C. under nitrogen for 17 hours and suction filtered through a 2.54 cm. pad of 70-230 mesh A.S.T.M. silica gel topped with a 7.62 cm. pad of Celite filter aid. The pads are washed with three 500 ml. portions of tetrahydrofuran, and the combined filtrate and washings are concentrated at 50° C. and reduced pressure to a volume of 150-200 ml. 500 ml. of n-heptane is added, the mixture is cooled to 0° C., and the resulting solids are collected by suction filtration, washed twice with n-heptane and vacuum dried at 45° C. to obtain the crude product as a pale yellow solid (54.0 g.).

Step 11 (Reaction I) Ethyl (±)-(E)-7-[1'-(4"-fluorophenyl)-4'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]-5-hydroxy-3-oxohept-6-enoate (Compound CXIII)

1.54 g. of 60% sodium hydride/mineral oil (38.5 mmoles) is washed twice with hexane, the remaining powdered sodium hydride is suspended in 100 ml. of dry tetrahydrofuran, the suspension is cooled to -20°--15° C., 4.55 g. (35.0 mmoles) of ethyl acetoacetate is added dropwise with stirring at -20°--15° C., the reaction mixture is stirred at -20°-15° C. for 30 minutes, 23.0 ml. of 1.6M. n-butyllithium/hexane (36.75 mmoles) is added dropwise with stirring at -20°--15° C., the reaction mixture is stirred at -20°--15° C. for 10 minutes, a solution of 5.857 g. (17.5 mmoles) of Compound CXII in 100 ml. of dry tetrahydrofuran is added dropwise with stirring at -20°--15° C., and the reaction mixture is stirred at -20°--15° C. for 30 minutes, the reaction mixture being maintained under dry argon throughout. The reaction mixture is quenched at -20°--15° C. with saturated ammonium chloride solution and warmed to 20° -25° C., the tetrahydrofuran is evaporated at reduced pressure, and the residue is partitioned between water and diethyl ether. The aqueous phase is reextracted with diethyl ether, and the diethyl ether phases are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to a yellow foam. The foam is flash chromatographed on 350 g. of 230-400 mesh A.S.T.M. silica gel utilizing 70% diethyl ether/hexane as the eluant to obtain the product as a yellow solid (7.91 g.).

The product is a racemate that may be resolved by conventional means to obtain the 5R and 5S enantiomers.

Step 12 (Reaction J) Ethyl (±)-erythro-(E)-3,5-dihydroxy-7-[1'-(4"-fluorophenyl)-4'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]hept-6-enoate (Compound CXIV)

(a) 34 ml. of 1.0M. tri-n-butylborane/tetrahydrofuran (34.0 mmoles) is added rapidly dropwise to a solution of 7.91 g. (17.0 mmoles) of Compound CXIII in 100 ml. of dry tetrahydrofuran (distilled from ketyl) stirred at 20°-25° C. under nitrogen, air is bubbled in for 1 minute, the reaction mixture is stirred at 20°-25° C. under nitrogen for 1 hour and cooled to -78° C., 3.22 g. (85.0 mmoles) of sodium borohydride is added in one portion, the reaction mixture is stirred at -78° C. under nitrogen for 16 hours, an additional 3.22 g. (85.0 mmoles) of sodium borohydride is added in one portion, and the reaction mixture is stirred at -78° C. under nitrogen for 64 hours, warmed to -25° C., stirred at -25° C. under nitrogen for 16 hours, quenched with 10% hydrochloric acid and partitioned between diethyl ether and water. The aqueous phase is neutralized with saturated sodium bicarbonate solution and extracted with diethyl ether. The two diethyl ether phases are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to a yellow wax (11.79 g.). The yellow wax is recrystallized from isopropanol to obtain a white powder (2.61 g.) which is recrystallized from isopropanol to obtain the cyclic boron ester as a white powder (1.83 g.).

(b) 4.0 g. of the cyclic boron ester of Part (a) of this step is dissolved in methanol with warming (35°-40° C.) and the methanol is evaporated at reduced pressure and 35°-40° C., this procedure is repeated two more times, the residue is dissolved in warm methylene chloride, and hexane is added to obtain the product as a white solid (2.93 g.). A second crop may be obtained from the mother liquor. M.p. 149°-151° C.

N.M.R. (CDCl₃): 1.26 (t, 3H), 1.36 (d, 6H), 1.61 (m, 2H), 2.45 (d, 2H), 3.13 (m, 1H), 3.23 (d, 1H), 3.30 (d, 1H), 4.16 (q, 2H), 4.19 (bm, 1H), 4.36 (bm, 1H), 5.50 (dd, 1H), 6.19 (dd, 1H), 7.0-7.37 (m, 9H)

The product, the erythro racemate, may be resolved to obtain the 3R,5S and 3S,5R enantiomers, of which the former is preferred. The use of a non-stereoselective reduction would afford a mixture of all four stereoisomers wherein the ratio of the erythro stereoisomers to the threo stereoisomers ranges from 3:2 to 2:3. A mixture of the erythro and threo racemates wherein the ratio of the former to the latter is about 7:3 may be obtained by omitting the isopropanol recrystallizations from Part (a) of this step.

EXAMPLE 2 Sodium (±)-erythro-(E)-3,5-dihydroxy-7-[1'-(4"-fluorophenyl)-4'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]hept-6-enoate (Reaction AA) ##STR17##

6.2 ml. of 1N. sodium hydroxide solution (6.2 mmoles) is added dropwise to a solution of 3.0 g. (6.52 mmoles) of Compound CXIV in 125 ml. of absolute ethanol stirred at 20°-25° C., the reaction mixture is stirred at 20°-25° C. for 2 hours and evaporated at reduced pressure to dryness, the residue is partitioned between water and methylene chloride, sufficient water is added to break the resulting emulsion, the aqueous layer is carefully separated, most of the water is evaporated at reduced pressure, and the resulting slurry is frozen at -78° C. and lyophilized to obtain the product as a pale yellow powder (3.02 g.), m.p. 217°-224° C. (dec.) (softens and loses water at 100°-116° C.).

N.M.R. (CDCl₃ +CD₃ SOCD₃): 1.32 (d, 6H), 1.53 (m, 2H), 2.30 (m, 2H), 3.13 (m, 1H), 4.08 (bm, 1H), 4.24 (bm, 1H), 5.50 (dd, 1H), 6.18 (dd, 1H), 7.0-7.3 (m, 9H)

The product, the erythro racemate, may be resolved to obtain the 3R,5S and 3S,5R enantiomers, of which the former is preferred. The use of a starting material synthesized by using a non-stereoselective reduction in Step 12 of Example 1 would afford a mixture of all four stereoisomers wherein the ratio of the erythro stereoisomers to the threo stereoisomers ranges from 3:2 to 2:3.

EXAMPLE 3 Ethyl (±)-erythro-(E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-1'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]hept-6-enoate ##STR18## Step 1 (Reaction DH) DL-4-Fluorophenylglycine (Compound CXIX)

800 ml. of saturated ammonium hydroxide solution is slowly added to 67.6 g. (1.59 moles) of lithium chloride, 268.8 g. (4.79 moles) of potassium hydroxide is slowly added portionwise (the addition being exothermic), and a solution of 18.4 g. (0.81 mole) of benzyltriethylammonium chloride in 400 ml. of methylene chloride is added, the reaction mixture being stirred at 20°-25° C. under nitrogen throughout. The reaction mixture is cooled to 0° C., ammonia is bubbled in for 30 minutes with vigorous stirring, and, over a period of 1 hour, a solution of 99.2 g. (0.80 mole) of 4-fluorobenzaldehyde in a mixture of 400 ml. of methylene chloride and 102 ml. of chloroform is added dropwise while simultaneously bubbling in ammonia, the reaction mixture being stirred at 0° C. throughout. Ammonia is bubbled in for 5 hours with stirring at 0° C., and the reaction mixture is allowed to warm to 20°-25° C. and stirred at 20°-25° C. for 16 hours. The aqueous phase is separated, washed three times with 150 ml. portions of methylene chloride, concentrated to one half of its volume at reduced pressure and filtered. The filtrate is acidified to pH 6.5 with concentrated hydrochloric acid, and the resulting fine precipitate is collected by filtration, washed with 1.5 l. of water, washed with 500 ml. of ethanol, washed with 200 ml. of diethyl ether and dried to obtain the product as a fine white solid (40 g.). A previous batch melted at about 280° C. (softened at about 260° C.).

Step 2 (Reaction CA) N-Benzoyl-DL-4-fluorophenylglycine (Compound CXX)

A solution of 23.2 ml. (28.1 g., 200 mmoles) of benzoyl chloride in 70 ml. of dioxane and 500 ml. of 2N. sodium hydroxide solution (1 mole) are simultaneously added dropwise over a period of about 45 minutes to a solution of 25.35 g. (150 mmoles) of Compound CXIX in a mixture of 300 ml. of dioxane and 600 ml. of 2N. sodium hydroxide solution (1.2 moles) stirred at 0° C. under nitrogen, the additions being at rates such that the pH of the reaction mixture is always basic and the temperature is 0° C., the reaction being exothermic. The reaction mixture is stirred at 0° C. under nitrogen for 1 hour and warmed to 20°-25° C., the tetrahydrofuran is evaporated at reduced pressure, and the mixture is acidified to pH 1 with concentrated hydrochloric acid and cooled to 0° C. The obtained white solid is collected by filtration, washed with 2 l. of distilled water, air dried and vacuum dried to obtain the product as a white powder (31.4 g.). An analytical sample is recrystallized from ethanol/water. M.p. 169°-171° C.

Step 3 (Reaction CB) (±)-N-[1-(4'-Fluorophenyl)-2-oxopropyl]benzamide (Compound CXXI)

50 ml. (618 mmoles) of pyridine and 50 ml. (530 mmoles) of acetic anhydride are added to 30 g. (110 mmoles) of Compound CXX, the mixture is stirred at 20°-25° C., 100 mg. (0.82 mmole) of 4-dimethylaminopyridine is added, the reaction mixture is stirred at 20°-25° C. for 45 minutes, 150 ml. (2.62 mmoles) of glacial acetic acid is added, and the reaction mixture is stirred at 130° C. for 3 hours and cooled to 20°-25° C., the reaction mixture being maintained under nitrogen throughout. The reaction mixture is cooled to 0°-5° C., 100 ml. of methanol is added, and the reaction mixture is stirred at 0°-5° C. for 30 minutes and poured into 1.5 l. of ice water. The mixture is allowed to stand for 16 hours, and the precipitate is collected by filtration, washed with 2 l. of distilled water and air dried to obtain a yellow powder which is recrystallized from methanol to obtain the yellow crystalline product (8.6 g.), m.p. 134°-136° C. A second crop is obtained from the mother liquor by adding water and cooling (2.5 g.).

Step 4 (Reaction CC) (±)-N-[1-(4'-Fluorophenyl)-2-(1'-methylethyl)iminopropyl]benzamide (Compound CXXII)

100 mg. (0.53 mmole) of p-toluenesulfonic acid monohydrate is added to a solution of 5.42 g. (20.0 mmoles) of Compound CXXI and 8.2 l. (5.69 g., 96.3 mmoles) of isopropylamine in 100 ml. of benzene and 25 ml. of methylene chloride, 25 g. (208 mmoles) of anhydrous magnesium sulfate is added, the reaction mixture is stirred at 20°-25° C. under nitrogen for 48 hours, an additional 16.4 ml. (11.38 g., 192.6 mmoles) of isopropylamine and 50 g. (415 mmoles) of anhydrous magnesium sulfate are added, the reaction mixture is stirred at 20°-25° C. under nitrogen for 4 hours, an additional 10 g. (42 mmoles) of anhydrous magnesium sulfate is added, and the reaction mixture is stirred at 20°-25° C. under nitrogen for 64 hours and filtered. The solid is washed with methylene chloride, the washing is combined with the filtrate, and the combined filtrate and washing is evaporated at reduced pressure to obtain the crude product as a yellow oil (about 7.5 g.).

Step 5 (Reaction CD) 4-(4'-Fluorophenyl)-5-methyl-1-(1'-methylethyl)-2-phenyl-1H-imidazole (Compound CXXIII)

A solution of about 7.5 g. (≦20 mmoles) of crude Compound CXXII from Step 4 in 50 ml. of chloroform is added over a 30 minute period to 8.12 g. (39 mmoles) of phosphorus pentachloride in 100 ml. of chloroform stirred at -30° C., and the reaction mixture is allowed to warm to 20°-25° C., stirred at 20°-25° C. for 16 hours and cooled to 0° C., the reaction mixture being stirred under nitrogen throughout. 10 ml. of water is added, the mixture is stirred for 5 minutes, and 200 ml. of 2N. sodium hydroxide solution is added. The organic phase is separated, and the aqueous phase is extracted with chloroform. The chloroform extract and the organic phase are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to a tan solid. The tan solid is recrystallized from benzene to obtain the product as a white solid (2.33 g.). A second crop is obtained from the mother liquor (200 mg.). An analytical sample is recrystallized from aqueous ethanol. M.p. 161°-162° C.

Step 6 (Reaction CE) 5-Acetoxymethyl-4-(4'-fluorophenyl)-1-(1'-methylethyl)-2-phenyl-1H-imidazole (Compound CXXIV)

3.5 g. (7.9 mmoles) of lead tetraacetate is added to a solution of 2.30 g. (7.81 mmoles) of Compound CXXIII in 300 ml. of dry benzene, and the reaction mixture is refluxed under nitrogen for 3 hours, an additional 0.35 g. (0.79 mmole) of lead tetraacetate is added, the reaction mixture is refluxed under nitrogen for 30 minutes, an additional 0.70 g. (1.58 mmoles) of lead tetraacetate is added, and the reaction mixture is refluxed under nitrogen for 1 hour, cooled, filtered and evaporated at reduced pressure to obtain the crude product as a tan gum (3.59 g.).

Step 7 (Reaction CF) 4-(4'-Fluorophenyl)-1-(1'-methylethyl)-2-phenyl-1H-imidazole-5-methanol (Compound CXXV)

100 ml. of 2N. sodium hydroxide solution (200 mmoles) is added to a solution of 3.59 g. (≦7.81 mmoles) of crude Compound CXXIV (from Step 6) in 100 ml. of ethanol, the reaction mixture is stirred at 20°-25° C. under nitrogen for 16 hours, the ethanol is evaporated at reduced pressure, 200 ml. of water is added, the mixture is stirred for 2 minutes, and the insoluble solid is collected by filtration, washed with 200 ml. of water (until the washings are pH 7) and dried to obtain the crude product as a yellow solid (1.88 g.). An analytical sample is recrystallized from aqueous ethanol. M.p. 190°-193° C.

Step 8 (Reaction CG) 4-(4'-Fluorophenyl)-1-(1'-methylethyl)-2-phenyl-1H-imidazole-5-carboxaldehyde (Compound CXXVI)

10 g. (115 mmoles) of activated manganese dioxide is added to a solution of 1.55 g. (5.0 mmoles) of Compound CXXV in 50 ml. of tetrahydrofuran, and the reaction mixture is stirred at 20°-25° C. under nitrogen for 16 hours and filtered. The solid is washed with 100 ml. of tetrahydrofuran, and the washing and filtrate are combined and evaporated at reduced pressure to obtain a yellow oil which is vacuum dried to obtain a yellow solid. The yellow solid is recrystallized from diethyl ether/hexane to obtain the yellow crystalline product (1.2 g.), m.p. 130°-134° C.

Step 9 (Reaction CK) Methyl (E)-3-[4'-(4"-fluorophenyl)-1'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]propenoate (Compound CXXVIII)

2.004 g. (6.0 mmoles) of (carbomethoxymethylene)triphenylphosphorane (Compound CXXVII) is added to a solution of 1.23 g. (4.0 mmoles) of Compound CXXVI in 25 ml. of dry toluene, the reaction mixture is refluxed under nitrogen for 5 hours and stirred at 20°-25° C. under nitrogen for 16 hours, an additional 200 mg. (0.6 mmole) of Compound CXXVII is added, and the reaction mixture is refluxed under nitrogen for 1 hour, allowed to cool, evaporated at reduced pressure to about one half of its volume and flash chromatographed on 150 g. of 230-400 mesh A.S.T.M. silica gel utilizing 1:1 diethyl ether/hexane as the eluant to obtain the product as a pale yellow solid (1.22 g.). An analytical sample is recrystallized from diethyl ether. M.p. 129°-131° C.

Step 10 (Reaction CL) (E)-3-[4'-(4"-Fluorophenyl)-1'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]prop-2-en-1-ol (Compound CXXIX)

10 ml. of 1.5M. diisobutylaluminum hydride/toluene (15 mmoles) is added dropwise over a period of 5 minutes to a solution of 1.092 g. (3.0 mmoles) of Compound CXXVIII in 50 ml. of dry tetrahydrofuran stirred at 0° C. under nitrogen, and the reaction mixture is stirred at 0° C. under nitrogen for 2 hours and quenched with 0.5 ml. of saturated ammonium chloride solution. 5 ml. of water is added to dissolve the precipitate, 100 ml. of saturated sodium chloride solution and 50 ml. of 10% sodium hydroxide solution are added, the organic phase is separated, the aqueous phase is extracted three times with 50 ml. portions of diethyl ether, and the organic phase and the three diethyl ether extracts are combined, washed with 100 ml. of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain the product as a colorless oil which solidifies upon standing (910 mg.).

Step 11 (Reaction CM) (E)-3-[4'-(4"-Fluorophenyl)-1'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]prop-2-enal (Compound CXXX)

8 g. (92 mmoles) of activated manganese dioxide is added to a solution of 900 mg. (2.68 mmoles) of Compound CXXIX in 100 ml. of 1:1 diethyl ether/tetrahydrofuran, and the reaction mixture is stirred at 20°-25° C. under nitrogen for 1 hour and filtered through a pad of Celite. The solid is washed with 100 ml. of diethyl ether and washed with 100 ml. of tetrahydrofuran, the two washings are combined with the filtrate, and the combined washings and filtrate are evaporated at reduced pressure to obtain a yellow oil (740 mg.) which solidifies upon standing. The solid is recrystallized from diethyl ether to obtain the product as yellow needles (405 mg). The residue from the mother liquor is recrystallized from aqueous ethanol to obtain a second crop (74 mg.) and a third crop (55 mg.). Additional product may be obtained by chromatographing the residue from the mother liquor from the third crop on 10 g. of silica gel utilizing 2:1 diethyl ether/hexane as the eluant (44 mg.).

Step 12 (Reaction I) Ethyl (±)-(E)-7-[4'-(4"-fluorophenyl)-1'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]-5-hydroxy-3-oxohept-6-enoate (Compound CXXXI)

21.12 mg. of 50% sodium hydride/mineral oil (0.44 mmole) is washed with 3 ml. of hexane, the liquid is decanted, 5 ml. of dry tetrahydrofuran is added, the suspension is cooled to -15° C., 51 μl. (52 mg., 0.40 mmole) of ethyl acetoacetate is added via syringe, the reaction mixture is stirred at -15° C. for 1.5 hours, allowed to warm to 0° C., stirred at 0° C. for 1 hour and cooled to -15° C., 0.31 ml. of 1.6M. n-butyllithium/hexane (0.50 mmole) is added with stirring at -15° C., the reaction mixture is stirred at -15° C. for 10 minutes, a solution of 66.8 mg. (0.20 mmole) of Compound CXXX in 3 ml. of dry tetrahydrofuran is added dropwise with stirring at -15° C., and the reaction mixture is stirred at - 15° C. for 15 minutes, the reaction mixture being maintained under nitrogen throughout. The reaction mixture is quenched at -15° C. with 5 drops of saturated ammonium chloride solution, the tetrahydrofuran is evaporated at reduced pressure, diethyl ether and saturated sodium chloride solution are added, and the organic layer is separated, washed twice with 25 ml. portions of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain a gum (92 mg.). The gum is chromatographed on 5 g. of 230-400 mesh A.S.T.M. silica gel utilizing 9:1 diethyl ether/hexane as the eluant to obtain the product as a pale yellow gum (39.1 mg.).

The product is a racemate that may be resolved by conventional means to obtain the 5R and 5S enantiomers.

Step 13 (Reaction J) Ethyl (±)-erythro-(E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-1'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]hept-6-enoate (Compound CXXXII)

A solution of 39 mg. (0.084 mmole) of Compound CXXXI in 1 ml. of anhydrous diethyl ether is added dropwise via syringe over a period of 5 minutes to 2.4 ml. of 0.15M. zinc borohydride/diethyl ether (0.36 mmole) stirred at -65° C. under nitrogen, and the reaction mixture is stirred at -65° C. under nitrogen for 2 hours and quenched at -65° C. with 0.5 ml. of methanol. The mixture is stirred for 3 minutes, 1 ml. of water is added, the mixture is allowed to warm to 20°-25° C., 10 ml. of very dilute acetic acid is added, 10 ml. of diethyl ether is added, and the organic phase is separated, washed twice with 20 ml. portions of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to a yellow oil. The yellow oil is chromatographed on 10 g. of 230-400 mesh A.S.T.M. silica gel utilizing 30% ethyl acetate/chloroform as the eluant. The fractions containing the product (as indicated by thin layer chromatography) are combined and evaporated at reduced pressure, and the obtained pale yellow oil is vacuum dried to obtain the product as a solid foam (31 mg.).

N.M.R. (CDCl₃): 1.28 (t, 3H), 1.48 (d, 6H), 1.56 (m, 2H), 2.46 (d, 2H), 4.18 (q, 2H), 4.21 (bm, 1H), 4.47 (bm, 1H), 4.59 (m, 1H), 5.78 (dd, 1H), 6.7 (d, 1H), 6.98 (t, 2H), 7.4-7.7 (m, 7H)

The product is a mixture of the erythro and threo racemates wherein the ratio of the former to the latter is about 17:3, which mixture may be separated by conventional means. The principal product, the erythro racemate, may be resolved into two optically pure enantiomers, the 3R,5S and 3S,5R enantiomers, of which the former is preferred. The minor product, the threo racemate, may be resolved to obtain the 3R,5R and 3S,5S enantiomers. The use of a non-stereoselective reduction would afford a mixture of all four stereoisomers wherein the ratio of the erythro stereoisomers to the threo stereoisomers ranges from 3:2 to 2:3.

EXAMPLE 4 Sodium (±)-erythro-(E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-1'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]hept-6-enoate (Reaction AA) ##STR19##

0.04 ml. of 0.5N. sodium hydroxide solution (0.02 mmole) is added to a solution of 10 mg. (0.0214 mmole) of Compound CXXXII in 1 ml. of ethanol and 10 drops of water, the reaction mixture is stirred at 20°-25° C. under nitrogen for 1 hour, the ethanol is evaporated at reduced pressure, 0.5 ml. of water is added, and the mixture is extracted three times with 5 ml. portions of diethyl ether. The aqueous phase is lyophilized to obtain the product as a pale yellow solid (9.8 mg.).

N.M.R. (CDCl₃ +CD₃ OD): 1.45 (d, 6H), 1.55 (m, 2H), 2.35 (m, 2H), 4.14 (bm, 1H), 4.40 (bm, 1H), 4.57 (m, 1H), 5.75 (dd, 1H), 6.67 (d, 1H), 6.98 (t, 2H), 7.4-7.7 (m, 7H)

The product is a mixture of the erythro and threo racemates wherein the ratio of the former to the latter is about 17:3, which mixture may be separated by conventional means. The principal product, the erythro racemate, may be resolved into two optically pure enantiomers, the 3R,5S and 3S,5R enantiomers, of which the former is preferred. The minor product, the threo racemate, may be resolved to obtain the 3R,5R and 3S,5S enantiomers. The use of a starting material synthesized by using a non-stereoselective reduction in Step 13 of Example 3 would afford a mixture of all four stereoisomers wherein the ratio of the erythro stereoisomers to the threo stereoisomers ranges from 3:2 to 2:3.

EXAMPLE 5 Ethyl (±)-(E)-3,5-dihydroxy-7-[1'-(4"-fluorophenyl)-4'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]hept-6-enoate.hydrochloride

(Reaction AL) ##STR20##

Hydrogen chloride is bubbled for 10 minutes through a solution of 18.5 mg. of Compound CXXXIV wherein the ratio of the erythro racemate to the threo racemate is about 7:3 in diethyl ether stirred at 20°-25° C., the diethyl ether is evaporated at reduced pressure, the resulting gum is dissolved in methylene chloride and the methylene chloride is evaporated at reduced pressure to obtain the product as a yellow foam. M.p. 85°-95° C.

The product is a mixture of the erythro and threo racemates wherein the ratio of the former to the latter is about 7:3.

EXAMPLE 6 Ethyl (±)-(E)-7-[1'-(4"-fluorophenyl)-4'-(1"-methylethyl)-2'-phenyl-1H-imidazol-5'-yl]-3-hydroxy-5-oxohept-6-enoate

(Reaction BA) ##STR21##

A solution of 200 mg. (0.43 mmole) of Compound CXIV in 10 ml. of tetrahydrofuran is stirred with 200 mg. (2.3 mmoles) of activated manganese dioxide for 40 minutes at 20°-25° C., the reaction mixture is filtered, and the filtrate is evaporated at reduced pressure. The residue is dissolved in a mixture of diethyl ether and methylene chloride, and hexane is added to crystallize the product. M.p. 120°-121° C.

                                      TABLE I                                      __________________________________________________________________________     Examples 7-32A                                                                 The following compounds of Groups IAa, ICa and IDa may be synthesized by       the processes set forth above:                                                 R.sub.1      R.sub.2   R.sub.3 X        R.sub.13                                                                          R.sub.14                                                                          Isomers                                                                               M.p.                      __________________________________________________________________________     Ex. 7                                                                                .sub.-i-C.sub.3 H.sub.7                                                               3,5-dimethylphenyl                                                                       phenyl  (E)--CH═CH--                                                                        H  C.sub.2 H.sub.5                                                                   E      73°-75°                                                           C.                       Ex. 8                                                                                .sub.-i-C.sub.3 H.sub.7                                                               3,5-dimethylphenyl                                                                       phenyl  (E)--CH═CH--                                                                        H  Na.sup.⊕                                                                      E      230°-235.degre                                                          e. C. (dec.)              Ex. 9                                                                                .sub.-i-C.sub.3 H.sub.7                                                               phenyl    phenyl  (E)--CH═CH--                                                                        H  C.sub.2 H.sub.5                                                                    E:T = ˜12:1                                                                    104°-110.degre                                                          e. C.                     Ex. 10                                                                               .sub.-i-C.sub.3 H.sub.7                                                               phenyl    phenyl  (E)--CH═CH--                                                                        H  Na.sup.⊕                                                                      E      215° C.                                                                 (dec.)                    Ex. 11                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-fluorophenyl                                                                           phenyl  --CH.sub.2 CH.sub.2 --                                                                  H  Na.sup.⊕                                                                      E      75°-85°                                                           C.                       Ex. 12                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-fluorophenyl                                                                           phenyl  --CH.sub.2 CH.sub.2 --                                                                  H  C.sub.2 H.sub.5                                                                   E      Foam                      Ex. 13                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-bromophenyl                                                                            phenyl  (E)--CH═CH--                                                                        H  C.sub.2 H.sub.5                                                                   E      132°-134.degre                                                          e. C.                     Ex. 14                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-chlorophenyl                                                                           phenyl  (E)--CH═CH--                                                                        H  CH.sub.3                                                                          E      132°-134.degre                                                          e. C.                     Ex. 15                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-chlorophenyl                                                                           phenyl  (E)--CH═CH--                                                                        H  Na.sup.⊕                                                                      E      183°-205.degre                                                          e. C.                     Ex. 16                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-bromophenyl                                                                            phenyl  (E)--CH═CH--                                                                        H  Na.sup.⊕                                                                      E      219°-226.degre                                                          e. C.                     Ex. 17                                                                               .sub.-i-C.sub.3 H.sub.7                                                               cyclohexyl                                                                               phenyl  (E)--CH═CH--                                                                        H  C.sub.2 H.sub.5                                                                   E      102°-106.degre                                                          e. C.                     Ex. 18                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-fluorophenyl                                                                            .sub.-t-C.sub.4 H.sub.9                                                               (E)--CH═CH--                                                                        H  C.sub.2 H.sub.5                                                                   E      Oil                       Ex. 19                                                                               .sub.- i-C.sub.3 H.sub.7                                                              4-fluorophenyl                                                                            .sub.-t-C.sub.4 H.sub.9                                                               (E)--CH═CH--                                                                        H  Na.sup.⊕                                                                      E      215°-220.degre                                                          e. C.                     Ex. 20                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-fluorophenyl                                                                           cyclohexyl                                                                             (E)--CH═CH--                                                                        H  C.sub.2 H.sub.5                                                                   E      86°-88°                                                           C.                       Ex. 21                                                                               .sub.-i-C.sub.3 H.sub.7                                                               cyclohexyl                                                                               phenyl  (E)--CH═CH--                                                                        H  Na.sup.⊕                                                                      E      145°-155.degre                                                          e. C.                     Ex. 22                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-fluorophenyl                                                                           cyclohexyl                                                                             (E)--CH═CH--                                                                        H  Na.sup.⊕                                                                      E      224°-226.degre                                                          e. C.                     Ex. 23                                                                               .sub.-i-C.sub.3 H.sub.7                                                               3,5-dichlorophenyl                                                                       phenyl  (E)--CH═CH--                                                                        H  CH.sub.3                                                                          E:T = ˜3:2                                                                      143°-145.degre                                                          e. C.                     Ex. 24                                                                               .sub.-i-C.sub.3 H.sub.7                                                               3,5-dichlorophenyl                                                                       phenyl  (E)--CH═CH--                                                                        H  Na.sup.⊕                                                                      E:T = ˜3:2                                                                      219°-225.degre                                                          e. C.                     Ex. 25                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-fluorophenyl                                                                           4-phenylphenyl                                                                         (E)--CH═CH--                                                                        H  C.sub.2 H.sub.5                                                                   E      177°-178.degre                                                          e. C.                     Ex. 26                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-fluorophenyl                                                                           4-phenylphenyl                                                                         (E)--CH═CH--                                                                        H  Na.sup.⊕                                                                      E      230°-235.degre                                                          e. C.                     Ex. 27                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-fluorophenyl                                                                           adamantyl-1                                                                            (E)--CH═CH--                                                                        H  C.sub.2 H.sub.                                                                    E:T = 83:17                                                                           Gum                       Ex. 28                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-fluorophenyl                                                                           styryl  (E)--CH═CH--                                                                        H  C.sub.2 H.sub.5                                                                   E      95°-97°                                                           C.                       Ex. 29                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-fluorophenyl                                                                            .sub.-i-C.sub.3 H.sub.7                                                               (E)--CH═CH--                                                                        H  C.sub.2 H.sub.5                                                                   E:T = ˜4:1                                                                      Gum                       Ex. 30                                                                               .sub.-i-C.sub.3 H.sub.7                                                               4-fluorophenyl                                                                            .sub.-i-C.sub.3 H.sub.7                                                               (E)--CH═CH--                                                                        H  Na.sup.⊕                                                                      E:T = ˜4:1                                                                      204°-205.degre                                                          e. C. (dec.)              Ex. 31                                                                              4-fluorophenyl                                                                         4-fluorophenyl                                                                           phenyl  (E)--CH═CH--                                                                        H  C.sub.2 H.sub.5                                                                   E      138°-139.degre                                                          e. C.                     Ex. 32                                                                              4-fluorophenyl                                                                         4-fluorophenyl                                                                           phenyl  (E)--CH═CH--                                                                        H  Na.sup.⊕                                                                      E      215°-220.degre                                                          e. C. (dec.)              Ex. 32A                                                                              .sub.- i-C.sub.3 H.sub.7                                                              4-fluorophenyl                                                                           phenyl  (E)--CH═CH--                                                                        H  CH.sub.3                                                                          E      156°-157.5.deg                                                          ree. C.                   __________________________________________________________________________      E = erythro racemate (≧ 95% pure (except Ex. 12: ≧90% pure)      balance, if any, threo racemate and/or impurities)                             T = threo racemate                                                       

                                      TABLE II                                     __________________________________________________________________________     Examples 33- 34                                                                The following compounds of Group IAb may be synthesized by the processes       set forth above:                                                               R.sub.1 R.sub.2 R.sub.3                                                                            X        R.sub.13                                                                          Isomers                                                                             M.p.                                      __________________________________________________________________________     Ex. 33                                                                              .sub.-i-C.sub.3 H.sub.7                                                           4-fluorophenyl                                                                         phenyl                                                                             (E)--CH═CH--                                                                        H  trans                                                                               160°-164° C.                Ex. 34                                                                              .sub.-i-C.sub.3 H.sub.7                                                           4-fluorophenyl                                                                         phenyl                                                                             --CH.sub.2 CH.sub.2 --                                                                  H  trans                                                                               209°-212° C.                __________________________________________________________________________      trans = trans racemate (≧ 95% pure)                               

                                      TABLE III                                    __________________________________________________________________________     Example 35                                                                     The following compound of Group IAc may be synthesized by the processes        set forth above:                                                               R.sub.1 R.sub.2 R.sub.3                                                                            X        Q  R.sub.13                                                                          R.sub.14                                                                          Isomers                                                                              M.p.                               __________________________________________________________________________     Ex. 35                                                                              .sub.-i-C.sub.3 H.sub.7                                                           4-fluorophenyl                                                                         phenyl                                                                             (E)--CH═CH--                                                                        CO H  Na.sup.⊕                                                                      Racemate                                                                             135°-150°            __________________________________________________________________________                                                 C.                            

N.M.R. DATA

Ex. 8 (CDCl₃ +CD₃ OD): 1.35 (d (J=7 Hz.), 6H), 1.35-1.70 (m, 2H), 2.26 (s, 6H), 2.10-2.40 (m, 2H), 3.15 (sp (J=7 Hz.), 1H), 3.50 (water), 4.08 (m, 1H), 4.28 (m, 1H), 5.50 (dd (J₁ =16 Hz., J₂ =6 Hz.), 1H), 6.18 (d (J=16 Hz.), 1H), 6.77 (s, 2H), 7.00 (s, 1H), 7.15-7.35 (m, 5H)

Ex. 9 (CDCl₃): 1.25 (t (J=1.5 Hz.), 3H), 1.36 (d, 6H), 1.6 (m, 2H), 2.45 (d, 2H), 3.15 (m, 1H), 3.17 (m, 1H), 3.7 (m, 1H), 4.15 (q (J=1.5 Hz.), 2H), 4.20 (m, 1H), 4.33 (m, 1H), 5.47 (dd (J₁ =1.5 Hz., J₂ =2 Hz.), 1H), 6.20 (d (J=3 Hz.), 1H), 7.10-7.45 (m, 10H)

Ex. 11 (CDCl₃): 1.11 (d (J=6 Hz.), 6H), 1.61 (m, 2H), 2.40 (bm, 6H), 2.88 (m, 1H), 3.46 (m, 1H), 3.95 (m, 1H), 7.1 (m, 9H)

Ex. 12 (CDCl₃): 1.28 (t (J=7 Hz.), 3H), 1.38 (d (J=7 Hz.), 6H), 1.64 (bs, 6H), 2.42 (d (J=7 Hz.), 2H), 2.58 (m, 1H), 3.7 (bs, 2H), 4.15 (q (J=7 Hz.), 2H), 7.0-7.3 (m, 9H)

Ex. 15 (CD₃ OD): 1.32 (d (J=7 Hz.), 6H), 1.4-1.8 (m, 2H), 2.2-2.4 (m, 2H), 3.22 (m, 1H), 3.93 (m, 1H), 4.25 (m, 1H), 5.58 (dd (J₁ =6 Hz., J₂ =16 Hz.), 1H), 6.22 (d (J=16 Hz.), 1H), 7.1-7.5 (m, 9H)

Ex. 16 (CD₃ OD): 1.35 (d (J=7 Hz.), 6H), 1.4-1.8 (m, 2H), 2.2-2.4 (m, 2H), 3.2 (m, 1H), 3.9 (m, 1H) 4.25 (m, 1H), 5.60 (dd (J₁ =6 Hz., J₂ =16 Hz.), 1H), 6.21 (d (J=16 Hz.), 1H), 7.1-7.7 (m, 9H)

Ex. 18 (CDCl₃): 1.19 (s, 9H), 1.25 (t (J=7 Hz.), 3H), 1.30 (d (J=7 Hz.), 6H), 1.4-1.9 (m, 2H), 2.43 (d (J=6 Hz.), 2H), 2.8-3.2 (m, 2H), 3.6 (m, 1H), 4.1-4.3 (m, 2H), 4.11 (q (J=7 Hz.), 2H), 5.20 (dd (J₁ =7 Hz., J₂ =16 Hz.), 1H), 5.88 (dd (J₁ =1 Hz., J₂ =16 Hz.), 1H), 7.0-7.3 (m, 4H),

Ex. 19 (CD₃ OD): 1.20 (s, 9H), 1.28 (d (J=7 Hz.), 6H), 1.3-1.7 (m, 2H), 2.2-2.3 (m, 2H), 3.11 (m, 1H), 3.8 (m, 1H), 4.12 (m, 1H), 5.26 (dd (J₁ =6 Hz., J₂ =16 Hz.), 1H), 5.96 (d (J=16 Hz.), 1H), 7.2-7.4 (m, 4H)

Ex. 21 (CD₃ OD): 1.1-2.1 (m, 12H), 1.22 (d (J=7 Hz.), 6H), 2.3-2.5 (m, 2H), 3.12 (m, 1H), 3.9-4.2 (m, 2H), 4.50 (m, 1H), 5.82 (dd (J₁ =6 Hz., J₂ =16 Hz.), 1H), 6.65 (d (J=16 Hz.), 1H), 7.4-7.5 (m, 5H)

Ex. 24 (CD₃ OD): 1.35 (d (J=7 Hz.), 6H), 1.5-1.8 (m, 2H), 2.2-2.4 (m, 2H), 3.2 (m, 1H), 3.9-4.1 (m, 1H), 4.3 (m, 1H), 5.5-5.7 (m, 1H), 6.2-6.4 (m, 1H), 7.3 (m, 7H), 7.6 (m, 1H)

Ex. 26 (CD₃ OD): 1.38 (d (J=7 Hz.), 6H), 1.5-1.8 (m, 2H), 2.3 (m, 2H), 3.33 (m, 1H), 3.95 (m, 1H), 4.27 (m, 1H), 5.56 (dd (J₁ =6 Hz.), J₂ =16 Hz.), 1H), 6.23 (d (J=16 Hz.), 1H), 7.2-7.6 (m, 13H)

Ex. 27 (CDCl₃): 1.23 (t (J=7 Hz.), 3H), 1.28 (d (J=7 Hz.), 6H), 1.4-1.7 (m, 8H), 1.9 (m, 8H), 2.4 (m, 2H), 2.94 (m, 1H), 3.04 (m, 1H), 3.60 (m, 1H), 4.17 (q (J=7 Hz.), 2H), 4.1-4.4 (m, 3H), 5.23 (dd (J₁ =6 Hz., J₂ =16 Hz.), 1H), 5.92 (d (J=16 Hz.), 1H), 7.1-7.3 (m, 4H),

Ex. 29 (CDCl₃): 1.1-1.3 (m, 15H), 1.4-1.7 (m, 2H), 2.4 (m, 2H), 2.70 (m, 1H), 3.08 (m, 1H), 3.7 (m, 2H), 4.7 (q (J=7 Hz.), 2H), 4.2-4.4 (m, 2H), 5.20 (dd (J₁ =7 Hz., J₂ =16 Hz.), 1H), 6.14 (dd (J₁ =1 Hz., J₂ =16 Hz.), 1H), 7.1-7.3 (m, 4H)

Ex. 32 (CD₃ OD): 1.2-1.7 (m, 2H), 2.2 (m, 2H), 3.8 (m, 1H), 4.2 (m, 1H), 5.41 (dd (J₁ 7 Hz., J₂ =16 Hz.), 1H), 6.43 (dd (J₁ =1 Hz., J₂ =16 Hz.), 1H), 7.1-7.4 (m, 11H), 7.6-7.8 (m, 2H)

Ex. 33 (CDCl₃ +CD₃ SOCD₃): 1.4 (d (J=7 Hz.), 6H), 1.6-2.0 (m, 2H), 2.62 (d (J=4 Hz.), 2H), 3.15 (m, 1H), 4.21 (m, 1H), 4.9 (bm, 1H), 5.2 (m, 1H), 5.5 (dd (J₁ =16 Hz., J₂ =7 Hz.), 1H), 6.28 (d, 1H), 7.1-7.4 (m, 9H)

Ex. 35 (CD₃ OD): 1.4 (d (J=7.5 Hz.), 6H), 2.28 (m, 4H), 3.2 (m, 1H), 4.28 (m, 1H), 5.95 (d (J=15 Hz.), 1H), 7.25 (m, 10H)

Each of the compounds identified by an E in the Isomers column is at least 95% pure (at least 90% in the case of Example 12) erythro racemate, the balance being the corresponding threo racemate and/or other impurities. Any threo racemate present may be separated therefrom. Each erythro racemate except those of Examples 11 and 12 may be resolved to obtain the 3R,5S and 3S,5R enantiomers, of which in each case the former is preferred. The erythro racemates of Examples 11 and 12 may be resolved to obtain the 3R,5R and 3S,5S enantiomers of which the former is preferred. The mixtures of Examples 9, 23, 24, 27, 29 and 30 may be separated to obtain the erythro and threo racemates, each of which may be resolved to obtain the 3R,5S and 3S,5R enantiomers from the former and the 3R,5R and 3S,5S enantiomers from the latter, the former being preferred in each case.

The compound of Example 33 may be resolved to obtain the 4R,6S and 4S,6R enantiomers, that of Example 34 may be resolved to obtain the 4R,6R and 4S,6S enantiomers, and that of Example 35 may be resolved to obtain the 3R and 3S enantiomers, the former being preferred in each case.

Each of the compounds of the examples wherein Z is a group of Formula a or c wherein R₁₄ is a cation may be converted into the corresponding compounds wherein R₁₄ is hydrogen or a different cation M, particularly the latter, especially M', by the processes set forth in Reaction Schemes IV and V. Each of the compounds of the examples except those wherein Z is a group of Formula a or c wherein R₁₄ is a cation and the one already in pharmaceutically acceptable acid addition salt form may be converted into pharmaceutically acceptable acid addition salt form as also set forth in Reaction Schemes IV and V.

Each of Examples 1-35 (including each of the possible optical isomers of each example) may be administered to an animal, e.g., a larger primate, to inhibit cholesterol biosynthesis and thereby lower the blood cholesterol level for, for example, the treatment of atherosclerosis and hyperlipoproteinemia. The dosages are those set forth supra.

Throughout the specification, the term "reduced pressure" denotes aspirator pressure. Where no solvent is specified in connection with a solution, the solvent is water, and all solvent mixtures are by volume. When a reaction is carried out under nitrogen or argon, dry nitrogen or argon, as the case may be, is used to maintain anhydrous conditions (except where the reaction medium contains water).

All nuclear magnetic resonance spectra were taken at ambient temperature on a 200 MHz. spectrometer. All chemical shifts are given in p.p.m. (δ) relative to tetramethylsilane, and where a single δ value is given for anything other than a sharp singlet, it is its center point. In the N.M.R. data:

bm=broad multiplet

bs=broad singlet

d=doublet

dd=doublet of a doublet

m=multiplet

q=quartet

s=singlet

sp=septet

t=triplet 

What is claimed is:
 1. A compound of the formula ##STR22## wherein R_(1a) is C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl, adamantyl-1 or ##STR23## R_(2a) is C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl, adamantyl-1 or ##STR24## R_(3a) is hydrogen, C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl, adamantyl-1, styryl or ##STR25## R₁₃ is hydrogen or C₁₋₃ alkyl, R'₁₆ is C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl or benzyl, andX is --CH₂ CH₂ --, --CH₂ CH₂ CH₂ --, --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH--, wherein each of R₄, R₇ and R₁₀ is independently hydrogen, C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl, C₁₋₃ alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy, each of R_(5a), R_(8a) and R_(11a) is independently hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, trifluoromethyl, fluoro, chloro, bromo, --COOR₁₈, --N(R₁₉)₂, phenoxy or benzyloxy, wherein R₁₈ is C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl or benzyl, and each R₁₉ is independently C₁₋₆ alkyl not containing an asymmetric carbon atom, and each of R₆, R₉ and R₁₂ is independently hydrogen, C₁₋₂ alkyl, C₁₋₂ alkoxy, fluoro or chloro, with the provisos that not more than one substituent on each of Rings A', B' and C' independently is trifluoromethyl, not more than one substituent on each of Rings A', B' and C' independently is phenoxy, and not more than one substituent on each of Rings A', B' and C' independently is benzyloxy.
 2. A compound according to claim 1 having the formula ##STR26## wherein X₃ is --CH₂ CH₂ -- or --CH₂ CH₂ CH₂ --.
 3. A compound according to claim 2 wherein X₃ is --CH₂ CH₂ --.
 4. A compound according to claim 1 having the formula ##STR27## wherein X₅ is --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH--.
 5. A compound according to claim 4 wherein X₅ is (E)--CH═CH--, (E)--CH═CH--CH₂ -- or (E)--CH₂ --CH═CH--.
 6. A compound according to claim 5 wherein X₅ is (E)--CH═CH--.
 7. A compound according to claim 6 wherein R_(1a) is C₁₋₃ alkyl, n-butyl or i-butyl, ##STR28## wherein R'₇ is hydrogen, C₁₋₃ alkyl, fluoro, chloro or bromo, R'_(8a) hydrogen, C₁₋₂ alkyl, fluoro or chloro, andR'₉ is hydrogen, or methyl, R_(3a) is ##STR29## R₁₃ is hydrogen, and R₁₆ is C₁₋₃ alkyl.
 8. A compound according to claim 7wherein R₁₀ is hydrogen, C₁₋₃ alkyl, C₁₋₂ alkoxy, trifluoromethyl, fluoro, chloro, bromo or phenyl, R_(11a) is hydrogen, C₁₋₂ alkyl, fluoro, chloro, bromo, --COOR'₁₈ or --N(R'₁₉)₂, wherein R'₁₈ is C₁₋₃ alkyl, and each R'₁₉ is independently C₁₋₂ alkyl, R₁₂ is hydrogen or methyl, and R₁₆ is C₁₋₂ alkyl.
 9. A compound according to claim 8wherein R_(1a) is C₁₋₃ alkyl, R'₇ is hydrogen, methyl or fluoro, R'_(8a) is hydrogen or methyl, R₁₀ is hydrogen, methyl or fluoro, and R_(11a) is hydrogen or methyl.
 10. A compound according to claim 9 wherein R_(1a) is i-propyl.
 11. A compound according to claim 9 having the erythro configuration.
 12. The 3R,5S enantiomer of a compound according to claim
 11. 